5, 5-disubstituted-1, 5-dihydro-4, 1-benzoxazepin-2 (3H)-ones useful as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to benzoxazepinones of formula I:                    
     or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same and methods of using the same for treating viral infection or as an assay standard or reagent.

This application is a division of U.S. patent application Ser. No. 09/145,101 filed Sep. 1, 1998, now U.S. Pat. No. 6,140,320 which claims benefit of U.S. Provisional Application No. 60/057,431 filed Sep. 2, 1997.

FIELD OF THE INVENTION

This invention relates generally to 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxythymidinene (d4T), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describes reverse transcriptase inhibitors which are benzoxazinones of the formula:

wherein X is a halogen, Z may be O. However, benzoxazinones are not part of the present invention.

U.S. Pat. No. 4,476,133 depicts CNS active 4,1-benzoxazepines of the formula:

wherein A-B can be NH—C(O), R is H or C₁₋₅ alkyl, X is H, halo, or NO₂, and Y is phenyl or pyridyl. No mention is made of 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are the subject of the present invention.

EP 0,142,361 illustrates phospholipase A₂ inhibitors of the formula:

wherein R₁ can be a variety of cyclic and acyclic groups, but not hydrogen, R₂ is H, alkyl, or phenyl, and Y₁ is H, halo, NO₂ or CF₃. Compounds of the present invention have a hydrogen at the 1-position and do not have a phenyl group directly attached to the 5-position.

EP 0,567,026 and JP 08/259,447, which have similar disclosures, describe 4,1-benzoxazepinone derivatives of the formula:

wherein ring A may be optionally substituted phenyl (also optionally substituted heteroaryl in JP '447), R₁, R₂, and R₃ can be a variety of groups including H and optionally substituted hydrocarbon, X is a bond or spacer and Y (B in JP '447) is optionally substituted carboxyl, hydroxyl, amino, phenyl, carbamoyl, or a nitrogen-containing heterocycle. In JP '447, B is only optionally substituted phenyl or nitrogen-containing heterocycle. Compounds of this sort are not within the presently claimed invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

wherein A, W, X, Y, Z, R^(a), R^(b), R¹ and R² are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

 or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is O or S;

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(a) is selected from H, CF₃, CF₂H, cycPr, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰;

R^(b) is selected from H, CF₃, CF₂H, cycPr, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰;

alternatively, R^(a) and R^(b) together form —(CH₂)_(n)—;

R¹ is selected from CF₃, CF₂H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R² is selected from —C≡C—R⁸, —CH═CR⁷R⁸, —(CH₂)_(p)CHR⁷R⁸, —CHR⁷C≡C—R⁸, —CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸;

provided that when either of R^(a) or R^(b) is phenyl, then R¹ is other than C₁₋₄ alkyl and C₃₋₅ cycloalkyl and R² is other than —(CH₂)_(p)CHR⁷R⁸;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7b), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form —OCH₂O— or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH2;

R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl;

R^(7a), at each occurrence, is selected from H and C₁₋₃ alkyl;

R^(7b), at each occurrence, is C₁₋₃ alkyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰;

R⁹, at each occurrence, is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰, at each occurrence, is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃;

R¹¹, at each occurrence, is selected from OR⁷, CN, F, Cl, Br, I, NO_(2,) NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂;

n, at each occurrence, is selected from 1, 2, 3, 4, and 5; and,

p, at each occurrence, is selected from 0, 1, and 2.

[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R^(a) is H;

R^(b) is selected from H, CF₃, CF₂H, cyclopropyl, CH═CH₂, and C₁₋₄ alkyl;

R¹ is selected from CF₃, CF₂H, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and,

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.

[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

A is O;

R¹ is selected from CF₃, CF₂H, C₂H₅, isopropyl, and cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7b), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—;

R⁵ is selected from H and F;

R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂;

R⁷ is selected from H and CH₃;

R^(7a) is selected from H and CH₃;

R^(7b) is CH₃;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; and,

p is selected from 1 and 2.

[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R^(b) is selected from H, CF₃, CF₂H, cyclopropyl, CH═CH₂, CH₃, and CH₂CH₃;

R¹ is selected from CF₃, CF₂H, and cyclopropyl;

R² is selected from —C≡C—R⁸ and trans-CH═CR⁷R⁸;

R³ is selected from H, F, Cl, Br, and I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH_(3,) C(O)CF_(3,) C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form —OCH₂O—; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂.

[5] In a further preferred embodiment, the compound of the present invention is selected from:

5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-S-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; and,

rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

 or a pharmaceutically acceptable salt form thereof.

[6] In another preferred embodiment, the present invention provides a compound of formula II:

 or a stereoisomer or pharmaceutically acceptable salt form thereof.

[7] In another more preferred embodiment, the present invention provides a compound of formula IIa:

 or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R¹ is CF₃.

In a second embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a third embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a fourth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, efavirenz, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, efavirenz, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the protease inhibitor is indinavir.

In a fifth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a sixth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

In a seventh embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

Definitions

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl”is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “aryl” or “aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be guaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, “HIV reverse transcriptase inhibitor” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, efavirenz (DuPont), rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697, 661, LY 73497, and Ro 18,893 (Roche).

As used herein, “HIV protease inhibitor” is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), DMP450 (DuPont), DMP850 (DuPont), DMP851 (DuPont) and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO94/19329, WO94/22840, and PCT Application Number US96/03426 and the protease inhibitors disclosed in WO94/04993,WO95/33464, WO96/28,418, and WO96/28,464.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference.

Scheme 1 illustrates a method of making the oxazepinones of the present invention starting from an appropriately substituted aminoalcohol. The amine is acylated by an α-halo acid halide (preferably an α-bromoacyl bromide) in the presence of a weak base such as pyridine. After acylation, cyclization is effected by further treatment with base. A tertiary amine base such as diisopropylethylamine, sodium hydride, potassium hydride, lithium hydride, sodium carbonate, potassium carbonate or cesium carbonate, sodium or potassium alkoxides or similar bases may be used with cesium carbonate and sodium hydride being preferred. Any non-protic organic solvent may be used for the cyclization reaction with DMF being preferred. In cases where R¹ and R² are different and R^(a) and R^(b) are also different, two diastereomers are formed which may be separated by selective crystallization or chromatography. In the case where R¹ and R² are different and either R^(a) or R^(b) is H, cyclization with cesium carbonate in the presence of lithium bromide or lithium iodide will often afford a diastereomeric mixture in which one diastereomer greatly predominates. Thus, in some cases these cyclization conditions are greatly preferred. In cases where both R^(a) and R^(b) are H, either sodium hydride or cesium carbonate are preferred bases. When an appropriately strong base is used, both acylation and cyclization reactions illustrated in Scheme 1 may be effected in a single step.

Scheme 2 illustrates a second method of making the oxazepinones of the present invention starting from an appropriately substituted N-tritylaminoalcohol. The hydroxy group is alkylated with an α-haloester in the presence of base, and then after removal of the trityl protecting group, treatment with base and/or heat effects cyclization to the oxazepinone. In some cases it may be preferable to use an unprotected amino group. Also, other protecting groups known to those of skill in the art can be used in place of the shown trityl group.

Scheme 3 illustrates a method of making 5,5-disubstituted-benzoxazepin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. In Scheme 3, G can be R³, R⁴, R⁵ or R⁶ or a combination of two or more of these groups. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R¹-substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized by the 2-step procedure described in Scheme 1.

Scheme 4 describes a means of obtaining 5-trifluoromethyl-benzoxazepin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 5-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1.

Because certain benzo-substituents are incompatible with the methods of the previous schemes, it may be necessary to protect these groups before forming the benzoxazepinone. In Scheme 5 there is shown a means of obtaining carbonyl-substituted 5,5-disubstituted-benzoxazepin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 4 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art.

A method for forming 5,5-disubstituted-benzoxazepin-2-ones, wherein R² is a vinyl or alkynyl group, is described in Scheme 6. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 3 or 4, an acetylide is added. The product can be deprotected and cyclized in two steps (Scheme 1) to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH₄, deprotection by standard means, and 2-step cyclization.

The acetylide which is required for the reactions illustrated in Scheme 6 may be generated directly from a terminal acetylene by treatment with a strong base such as n-butyllithium. An alternate method for generating an acetylide, illustrated in Scheme 6A, is by converting an aldehyde to a 1,1-dibromoolefin which is then reacted with 2 equivalents of n-butyllithium.

Scheme 7 describes an alternate route to 5,5-disubstituted-benzoxazepin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R² group can then be added, e.g. via an acetylide, followed by cyclization as in Scheme 1.

An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 4. Reduction and reoxidation removes the chloro group leaving the desired intermediate.

Scheme 9 describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 3, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group.

Scheme 10 illustrates specific steps of Scheme 9. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃CF₂, and CF₃CF₂CF₂) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF₃CF₂TMS, CF₃CF₂CF₂TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about −20° C. to about 50° C., preferably about −10 to about 10° C., more preferably about 0° C.

Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO₂, PDC, PCC, K₂Cr₂O₇, CrO₃, KMnO₄, BaMnO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant is MnO₂. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane, dichloroethane, or tetrachloroethane, preferably dichloromethane.

An additional means of making 5-alkynyl-benzoxazepin-2-ones is shown in Scheme 11. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound.

In addition to the methods of obtaining keto-anilines described in Schemes 3 and 4, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 12. This reaction is accomplished by using an anionic nucleophile of the group R^(1a). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from −20 to +35° C., with temperatures below 0° C. being more preferred and −20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent.

Scheme 13 illustrates the synthesis of a 3,3-disubstituted oxazepinone from a monosubstituted oxazepinone. After first protecting the ring nitrogen with one of several amide protecting groups known to those skilled in the art, treatment with a strong base followed by an alkyl iodide gives after protecting group removal, a 3,3-disubstituted oxazepinone. Using the same sequence of reactions, a 3-monosubstituted oxazepinone (R^(a) above is H) can also be synthesized from a 3-unsubstituted oxazepinone.

Compounds of the present invention that are thioamides can be prepared as illustrated in Scheme 14 by treating the corresponding amides with either Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] or phosphorous pentasulfide.

Compounds of the present invention in which R^(a) or R^(b) are vinyl or cyclopropyl can be prepared as illustrated in Scheme 15. 2-Aminoarylketones protected, for example, with an N-p-methoxybenzyl (PMB) group can be treated with an acetylide to give the corresponding acetylenic alcohol. Cyclization can be effected by 2,4-dibromobutyryl chloride and the PMB group can then be removed, for example, by treatment with ceric am monium nitrate. Displacement of the bromide with an arylselenide followed by oxidative elimination by treatment with hydrogen peroxide affords the 5-alkynyl-3-vinylbenzoxazepinone. The vinyl group can be converted to a cyclopropane ring by Pd(II) catalyzed reaction with diazomethane. If the acetylenic alcohol is reduced to the olefin with lithium aluminum hydride (LAH), the same reaction sequence can be used to prepare the trans-5-alkenyl-3-vinylbenzoxazepinone and the corresponding trans-5-alkenyl-3-cyclopropylbenzoxazepinone.

One isomer of a compound of Formula I may display superior activity compared with the other. Thus, all four of the following stereochemistries are considered to be a part of the present invention.

When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. Lett. 1995, 36, 8937-8940. In addition, separation may be achieved by selective cystallization, optionally in the presence of a chiral acid or base thereby forming a chiral salt. other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: anal. for combustion analysis, “g” for gram or grams, HRMS for high resolution mass spectrometry, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimole or millimoles, “h” for hour or hours, “HPLC” for high performance liquid chromatography, “M” for molar, “min” for minute or minutes, “MHz” for megahertz, “MS” for mass spectroscopy, “TLC” for thin layer chromatography.

For further clarification of the stereochemistry, in compounds with stereochemistry designated as “rel-(3S,5S)” the 3-substituent is cis to the 5-trifluoromethyl group while in compounds with stereochemistry designated as “rel-(3R,5S)” the 3-substituent is trans to the 5-trifluoromethyl group.

Example 1

Preparation of 5-(1-Butynyl)-7-chloro-1,5-dihydro-5(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

Part A: Preparation of 1-(5-Chloro-2triphenylmethylanino)phenyl-2,2,2-trifluoroethanone

1-(2-Amino-5-chlorophenyl)-2,2,2-trifluoroethanone (see U.S. Pat. No. 5,519,021)(22.4 g, 100 mmol), trityl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and 4-(dimethylamino)pyridine (0.5 g, 4 mmol) were dissolved in DMF (50 mL) and held 14 h at 60° C. The resulting slurry was cooled to room temperature, diluted with 20 mL water and filtered to give 35.9 g (77%) of the title compound.

Part B: Preparation of 6-Amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol

To a −30° solution of 1.4 g of 1-butyne in 30 mL of dry THF was added dropwise over S min, 7.5 mL of a 1.6 M solution of n-butyllithium in hexane. The reaction mixture was allowed to warm to 0° and then stirred at this temperature for 30 min after which time 1.4 g of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone was added in one portion. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to a pure solid. This material was was dissolved in 20 mL of methanol and treated with 0.370 mL of 12 N aqueous hydrochloric acid for 15 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried and evaporated. The residue was dissolved in methanol and after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from hexanes afforded 675 mg of the title compound as a crystalline solid.

Part C: Preparation of 5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 167 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.066 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF and was treated at room temperature with 25 mg of 100% sodium hydride for 1.5 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was purified by preparative silica gel TLC (elution with ethyl acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 106 mg of the title compound as colorless crystals: mp 167-168°; Anal. Calcd. for C₁₄H₁₁NO₂ClF₃: C, 52.93; H, 3.49; N, 4.42. Found: C, 52.73; H, 3.64; N, 4.13.

Example 2

Preparation of rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluormethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 278 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol (Example 1, Part B) in 25 mL of dry ether was added 0.150 mL of dry pyridine and 0.200 mL of α-chlorophenacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 50 mg of potassium iodide and 28 mg of 100% sodium hydride were added and this solution was heated at 60° for 12 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was subjected to column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3) affording a mixture of diastereomers. These were separated by column chromatography over silica gel (elution with 1% methanol in methylene chloride) and the less polar isomer (27 mg) was crystallized from hexane to give 13 mg of the title compound as colorless crystals: mp 198-199°; HRMS Calcd. for C₂₀H₁₆NO₂CF₃ (M+H)⁺: 394.082166. Found: 394.080316.

Example 3

Preparation of 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 3.06 g (45 mmol) of isopropylacetylene in 90 mL of dry THF was added dropwise over 5 min, 25 mL of a 1.6 M solution of n-butyllithium in hexane (40 mmol). After 30 min at 0°, a solution of 9.3 g of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone (Example 1, Part A) in 40 mL of dry THF was added dropwise over 5 min. The reaction mixture was stirred at 0° for 15 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to a pure solid. This material was was dissolved in 100 mL of methanol and treated with 2.0 mL of 12 N aqueous hydrochloric acid for 15 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried, and evaporated. The residue was dissolved in 200 mL of methanol and after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from 80 mL of hexanes afforded 4.40 g (75.4%) of the title compound as a crystalline solid.

Part B: Preparation of 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 4.37 g (15 mmol) of 6-amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 200 mL of dry ether was added 2.4 mL of dry pyridine and, quickly dropwise, 1.40 mL (16 mmol) of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 150 mL of dry DMF and was treated at 0° with 400 mg of 100% sodium hydride (16.7 mmol) for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1.5 h. The reaction mixture was poured onto a mixture of 1.2 L of water and 300 mL of saturated aqueous sodium chloride and this was extracted 3 times with ether. The combined extracts were washed with brine, dried, and evaporated to a solid which was crystallized by dissolving in hot ethyl acetate and adding hexanes. This material was recrystallized from ethyl acetate/hexane to afford 3.125 g of pure title compound as a crystalline solid: mp 183-183.5°; HRMS Calcd. for C₁₅H₁₄NO₂ClF₃ (M+H)⁺: 332.066516. Found: 332.065892.

Example 4

Preparation of (+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The racemic material from Example 3, Part B above was separated by preparative HPLC on a Chiralcel column maintained at ambient temperature with elution with 10% isopropylamine in carbon dioxide at a pressure of 150 Atm. and a flow rate of 2.0 mL/min. The slower moving isomer was collected and crystallized from hexane: mp 135-136°; [α]²⁵+9.69°.

Example 5

Preparation of trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 3-Chloro-6-(triphenylmethyl)amino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 4.5 g (67.55 mmol) of cyclopropylacetylene in 130 mL of dry THF was added dropwise over 5 min, 37.5 mL (60 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to warm to 0° over 30 min after which time a solution of 13.95 g (30.0 mmol) of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone (Example 1, Part A) in 50 mL of dry THF was added dropwise over 5 min. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to pure title compound as a glassy solid.

Part B: Preparation of trans-6-Amino-3-chloro-α-(2-cyclopropylethenyl)-α-(trifluoromethyl)benzyl alcohol

The reaction product from part A was dissolved in 100 mL of dry THF and treated overnight with 20 mL of a 1 M solution of lithium aluminum hydride in THF. At this time TLC showed incomplete reaction so an aditional 10 mL of 1 M lithium aluminum hydride was added. After 30 min the reaction was quenched by the addition of 0.800 mL of concentrated aqueous ammonium hydroxide. After gas evoution ceased, the mixture was diluted with ether, filtered through celite, and evaporated. The residue was dissolved in 150 mL of methanol and treated with 3.0 mL of 12 N aqueous hydrochloric acid for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted twice with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in 100 mL of boiling methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. The filtrate was evaporated to a solid which was suspended in 100 mL of boiling hexane. Pure colorless crystals of the title compound (4.04 g) were collected from the cooled mixture.

Part C: Preparation of trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 230 mg of trans-6-amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.140 mL of dry pyridine and 0.075 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at 0° with 24 mg of 100% sodium hydride. After 15 min the cooling bath was removed and stirring was continued at ambient temperature for 3 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The crude product was purified by column chromatiography over silica gel (elution with ethyl acetate/hexanes 1:3) affording after crystallization from ethyl acetate/hexanes 127 mg of the title compound as colorless crystals: mp 157-158°; HRMS Calcd. for C₁₅H₁₄NO₂ClF₃ (M+H)⁺: 332.066516. Found: 332.064517.

Example 6

Preparation of rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 291 mg of trans-6-Amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part C) in 13 mL of dry ether was added 0.180 mL of dry pyridine and 0.120 mL of bromopropionyl bromide. After 1 h, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 40 mg of 100% sodium hydride. After 15 min the cooling bath was removed and stirring was continued at ambient temperature for 20 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in a small amount of ethyl acetate, and addition of hexane resulted in the crystallization of 40 mg of the title compound as colorless crystals: mp 171-172°; HRMS: Calcd. for C₁₆H₁₆NO₂ClF₃ (M+H)⁺: 346.082166. Found: 346.080681. A second crop of slightly less pure product weighed 41 mg.

Example 7

Preparation of 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of N-(4-Fluorophenyl)-2,2-dimethylpropanamide

To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organic layer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid.

Part B: Preparation of 1-(2-Amino-5-fluorophenyl)-2,2,2-trifluoroethanone

To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid.

Part C: Preparation of 6-Amino-3-fluoro-α-isopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 1.89 mL of isopropylacetylene in 35 mL of dry THF was added dropwise over 5 min, 10.0 mL of 1.6 M n-butyllithium. The reaction mixture was stirred at 0° for 30 min after which time 828 mg of 1-(2-amino-5-fluorophenyl)-2,2,2-trifluoroethanone was added. The reaction mixture was stirred at 0° for 1.25 h after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate/hexanes) affording 220 mg of the title compound as a tan solid.

Part D: 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 210 mg of 6-Amino-3-fluoro-α-isopropylethynyl-α-(trifluoromethyl)benzyl alcohol in 20 mL of dry ether was added 0.120 mL of dry pyridine and 0.080 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 20 mL of dry DMF and was treated at room temperature with 33 mg of 100% sodium hydride for 30 min. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 89 mg of the title compound as colorless crystals: mp 172-173°; Anal. Calcd. for C₁₅H₁₃NO₂F₄: C, 57.15; H, 4.17; N, 4.44. Found: C, 57.10; H, 3.98; N, 4.21.

Example 8

Preparation of 1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

A solution of 32 mg of 7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2-one in 4 mL of ethanol was stirred under 1 atmosphere of hydrogen in the presence of 5 mg of 10% palladium on carbon for 12 h. Filtration and evaporation afforded a solid material which was recrystallized from ethyl acetate/hexanes to afford 18 mg of the title compound as colorless crystals: HRMS: Calcd. for C₁₅H₁₈NO₂F₄ (M+H)⁺: 320.127367. Found: 320.127936.

Example 9

Preparation of rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 1,1-dibromo-2-furan-2-yl-ethylene

To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry methylene chloride at 0° was added 15.2 g (58 mmol) of triphenylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to −78°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a −70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.

Part B: Preparation of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol

To a solution of 2.88 g (11.4 mmol) of 1,1-dibromo-2-furan-2-ylethene in 40 mL of dry THF at −20° was added dropwise over 5 min, 14.25 mL (22.8 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to warm to 0° over 30 min at which time a solution of 4.2 g (9.0 mmol) of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone in 12 mL of dry THF was added dropwise over 1 min. The reaction mixture was stirred at 0° for 30 min after which time it was poured onto saturated aqueous ammonium chloride. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to 5.6 g of 3-chloro-6-(triphenylmethy)amino-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol as a dark colored solid.

Part C: Preparation of trans-6-Amino-3-chloro-(2-furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 3.35 g of 3-chloro-6-(triphenylmethy)amino-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 25 mL of dry THF was added 6 mL of 1.0 M lithium aluminum hydride in THF. After 1 h the reaction was quenched by the addition of 0.54 mL of concentrated aqueous ammonium hydroxide. After gas evolution ceased, the mixture was diluted with ether, filtered through celite, and evaporated. The residue was dissolved in 30 mL of methanol and treated with 0.70 mL of 12 N aqueous hydrochloric acid for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h and the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from hexanes afforded 888 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol as crystals.

Part D: Preparation of rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 317 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.125 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 489 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 24 h. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to 350 mg of crude product from which 108 mg of a single isomer could be isolated by crystallization (ethyl acetate/hexanes). This material was purified further on a short silica gel column, and then recrystallized from ethyl acetate/hexanes to give 86 mg of the title compound as colorless crystals: mp 205-206.5°; Anal. Calcd. for C₁₇H₁₃NO₃F₃Cl: C, 54.93; H, 3.54; N, 3.78. Found: C, 54.83; H, 3.40; N, 3.61.

Example 10

Preparation of trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 159 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 9, Part C) in 8 mL of dry ether was added 0.050 mL of dry pyridine and 0.055 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried, and evaporated. The residue was dissolved in 8 mL of dry DMF, 245 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 1.5 h. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product from which 86 mg of crystalline material was obtained (ethyl acetate/hexanes). This material was purified further on a short silica gel column (elution with ethyl acetate/hexanes 1:1), and then recrystallized from ethyl acetate/hexanes to give 68 mg of title compound: mp 199-200°; Anal. Calcd. for C₁₆H₁₁NO₃F₃Cl: C, 53.72; H, 3.11; N, 3.93. Found: C, 54.09; H, 3.35; N, 3.83.

Example 11

Preparation of rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-(furan-2yl)ethynyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 2.0 g of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol (Example 9, Part B) in 20 mL of methanol was added 0.125 mL of 12 N aqueous hydrochloric acid, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the residue was chromatographed over silica gel (elution with hexanes/ethyl acetate 3:1) affording after crystalization from hexane/ethyl acetate 280 mg of the title compound.

Part B: Preparation of rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 265 mg of 6-amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.150 mL of dry pyridine and 0.100 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF at 0°, 25 mg of 100% sodium hydride was added, and the resulting mixture was stirred for 15 min at 0° and at room temperature for 30 min. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to a residue which was purified by column chromatography on silica gel (elution with 17-33% ethyl acetate in hexanes) affording after crystallization from ethyl acetate/hexanes 5 mg of the title compound: HRMS: Calcd. for C₁₇H₁₂NO₃C₁F₃ (M+H)⁺: 369.037956. Found: 369.036835.

Example 12

Preparation of 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 465 mg (1 mmol) of 1-(5chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone in 15 mL of dry THF was added dropwise 2 mmol of n-butylmagnesium chloride in ether. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to a pure solid. This material was was dissolved in 10 mL of methanol and treated with 0.100 mL of 12 N aqueous hydrochloric acid for 1 h. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried and evaporated. Crystallization from hexanes afforded 195 mg of the title compound as a crystalline solid.

Part B: Preparation of 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 185 mg of 6-amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol in 15 ML of dry ether was added 0.100 mL of dry pyridine and 0.060 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at room temperature with 40 mg of 100% sodium hydride for 16 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried, and evaporated. The crude product was purified first by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3), and then by preparative silica gel TLC (elution with 2.5% methanol in methylene chloride) affording 32 mg of the title compound as an amorphous solid: HRMS: Calcd. for C₁₄H₁₆NO₂ClF₃ (M+H)⁺: 322.082166. Found: 322.080685.

Example 13

Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one Part A: Preparation of N-triLethylacetyl-3,4-difluoroanilide

To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92% yield).

Part B: Preparation of N-TriLmethylacetyl 5,6-difluoro-2-trifluoroacetylanilide.

To a solution of N-trimethylacetyl-3,4-difluoroanilide (4.0 g, 14.6 mmol) in THF (60 mL) at −78° C. was added dropwise 1.6M nBuLi in hexane (22 mL, 35 mmol) and the resulting reaction mixture was allowed to stir at −78° C. for 1 h. Ethyl trifluoroacetate (4 mL, 33.6 mmol) was added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline.

To a solution of the orange oil in dimethoxyethane (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na₂CO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellow solid (3285 mg theoretical, 64% yield).

Part D: Preparation of 1-(2,3-difluoro-6-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone

A solution of 500 mg of 5,6-Difluoro-2trifluoroacetylaniline, 693 mg of triphenylmethanol, and 8 mg of p-toluenesulfonic acid in 50 mL of toluene was heated a reflux for 3.5 h using a Dean-Stark trap for water separation. After evaporation of thhe solvent, the residue was purified by column chromatography over silica gel (5% ethylacetate in hexanes as eluent) affording 760 mg of the title compound as a yellow foam.

Part E: Preparation of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 250 mg of isopropylacetylene in 10 mL of dry THF was added dropwise 1.90 mL of a 1.6 M solution of n-butyllithium in hexane. After 30 min at 0°, 450 mg of 1-(2,3-difluoro-6-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone in 3 mL of dry THF was added quickly dropwise. The reaction mixture was stirred at 0° for 20 min after which time it was poured onto saturated aqueous ammonium chloride. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to an orange solid. 248 mg of this material was was dissolved in 5 mL of methanol and treated with 0.05 mL of 12 N aqueous hydrochloric acid for 20 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried, and evaporated. The crude product was purified by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3) affording 81 mg of the title compound.

Part F: Preparation of 6,7-Difluoro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 81 mg of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 8 mL of dry ether was added 0.55 mL of dry pyridine and 0.032 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 10 mg of 100% sodium hydride for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1 h. The reaction was quenched with one drop of acetic acid and then the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and this solution was washed with water and brine, dried and evaporated to a solid which was crystallized from ethyl acetate/hexanes affording 28 mg of the title compound as colorless crystals: mp 192.5-193.5°; HRMS: Calcd. for C₁₅H₁₃NO₂F₅ (M+H)⁺: 334.086645. Found: 334.084917.

Example 14

Preparation of rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (Example 14a) and rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (Example 14b) Part A: Preparation of 6-Amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 3.0 g of 3-Chloro-6-30 (triphenylmethyl)amino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 5, Part A) in 30 mL of methanol was added 0.60 mL of 12 N aqueous hydrochloric acid, and this mixture was stirred at ambient temperature for 10 min. The reaction mixture was poured onto aqueous bicarbonate and extracted twice with ether. The combined extracts were washed withh brine, dried, and evaporated. The residue was dissolved in 20 mL of methanol and after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the crude solid was recrystallized from hexanes affording 1.16 g of the title compound as a purple solid.

Part B: Preparation of rel-(3S,5S)-7-Chloro-5cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one and rel-(3R,5S)-7-Chloro-5cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 220 mg of α-bromobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to 300 mg of crude product. This material was subjected to column chromatography over silica gel (elution with 5-25% ethyl acetate in hexanes) affording after crystallization from ethyl acetate/hexanes: 115 mg of rel-(3S,5S)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one as colorless crystals: mp 191-192°; Anal. Calcd. for C₁₈H₁₇NO₂F₃Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 57.89; H, 4.61; N, 3.60, and 25 mg of rel-(3R,5S)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one: mp 141°; HRMS: Calcd. for C₁₈H₁₈NO₂F₃Cl (M+H)⁺: 372.097816. Found: 372.096539.

Example 15

Preparation of rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C₁₈H₁₇NO₂F₃Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70.

Example 16 7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7, except that diisopropylethylamine was used as a base rather than sodium hydride: mp 190-191°; Anal. Calcd. for C₁₈H₁₁NO₂F₃Cl: C, 59.11; H, 3.03; N, 3.84. Found: C, 58.95; H, 3.12; N, 3.83.

Example 17 rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 181-182.8°; Anal. Calcd. for C₁₆H₁₅NO₂F₃Cl: C, 55.58; H, 4.37; N, 4.05. Found: C, 55.37; H, 4.39; N, 3.87.

Example 18 7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 199.5-200.5°; Anal. Calcd. for C₁₅H₁₁NO₂F₃Cl: C, 54.64; H, 3.36; N, 4.26. Found: C, 54.46; H, 3.17; N, 4.03.

Example 19 7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 168-1690; Anal. Calcd. for C₁₆H₁₆NO₂F₃Cl: C, 58.72; H, 4.94; N, 4.29. Found: C, 58.68; H, 4.90; N, 4.29.

Example 20 trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 5: mp 148-149°; HRMS: Calcd. for C₁₅H₁₆NO₂F₃Cl (M+H)⁺: 334.082166. Found: 334.081071.

Example 21 7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 8: mp 129-130°; Anal. Calcd. for C₁₆H₂₀NO₃F_(3:) C, 58.00; H, 6.08; N, 4.24. Found: C, 57.86; H, 5.95; N, 4.12.

Example 22 rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was obtained along with the title compound of Example 23 by a procedure similar to that of Example 7: mp 180-181°; Anal. Calcd. for C₁₇H₁₅NO₂F₃Cl: C, 57.07; H, 4.24; N, 3.93. Found: C, 56.85; H, 4.04; N, 3.95.

Example 23 rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was obtained along with the title compound of Example 22 by a procedure similar to that of Example 7: mp 129-130°; HRMS. Calcd. for C₁₇H₁₅NO₂F₃Cl (M+H)⁺: 358.082166. Found: 358.081980.

Example 24 7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that sodium hydrid rather than cesium carbonate was the base used in the final reaction step: mp 219-221°; HRMS: Calcd. for C₁₇H₁₁N₂ _(O) ₂F₃Cl (M+H)⁺: 367.046115. Found: 367.046761.

Example 25 trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 9 except that sodium hydride rather than cesium carbonate was the base used in the final reaction step: mp 199-201°; HRMS: Calcd. for C₁₇H₁₃N₂O₂F₃Cl (M+H)⁺: 369.061765. Found: 369.060918.

Example 26 trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 5: mp 145-156°.

Example 27 trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 5: mp 159-160°; HRMS: Calcd. for C₁₅H₁₅NO₂F₅ (M+H)⁺: 336.102295. Found: 336.102028.

Example 28 rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 14: mp 169-174°; HRMS: Calcd. for

Example 29 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 987 mg of trans-6-amino-3 -chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine and 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title compound: mp 171-172°; HRMS: Calcd. for C₁₆H₁₆₈NO₂F₃Cl (M+H)⁺: 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C₁₇H₁₈NO₂F₃Cl (M+H)⁺: 360.097816. Found: 360.097869

Example 30 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product Example 29: mp 167-167° HRMS: Calcd. for C₁₈H₁₉NO₂F₃Cl (M+H)⁺: 374.113467. Found: 374.114742.

Example 31 rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 214-215°.

Example 32 rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 169-170°; HRMS: Calcd. for C₁₈H₁₄NO₃F₃Cl (M+H)⁺: 384.061431. Found: 384.058632.

Example 33 rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 14: mp 219-220°.

Example 34 rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 14: mp 180.4-181.4°.

Example 35 rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoramethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 6 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 192-193°; HRMS: Calcd. for C₁₆H₁₅NO₂F₅ (M+H)⁺: 348.102295. Found: 348.102515.

Example 36 (+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 28 in a manner similar to the procedure described in Example 4: mp 145-146°; Anal. Calcd. for C₁₆H₁₃NO₂F₃Cl C, 55.91; H, 3.81; N, 4.07. Found: C, 55.80; H, 3.75; N, 3.88. [α]²⁵ +94.200.

Example 37 (3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 18 in a manner similar to the procedure described in Example 4: mp 135-136°; Anal. Calcd. for C₁₅H₁₁NO₂F₃Cl C, 54.64; H, 3.36; N, 4.26. Found: C, 54.69; H, 3.17; N, 4.00.

Example 38 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29 ; mp 147-147.5°; HRMS: Calcd. for C₁₇H₁₈NO₂F₃Cl (M+H)⁺: 360.097816. Found: 360.097869

Example 39 (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 29 in a manner similar to the procedure described in Example 4: mp 175-175.5°; Anal. Calcd. for C₁₆H₁₅NO₂F₃Cl C, 55.58; H, 4.37; N, 4.05. Found: C, 55.38; H, 4.21; N, 3.83. [α]²⁵ +61.70.

Example 40 (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 38 in a manner similar to the procedure described in Example 4: mp 163-1640; [α]²⁵ +22.7°.

Example 41 rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 1-(5-Chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone

A mixture of 6.0 g of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone, 3.84 mL of 4-methoxybenzyl alcohol, 114 mg of p-toluensulfonic acid, and 25 mL of dry acetonitrile was heated at 80° for 3.5 hr. An additional 0.5 g of 4-methoxybenzyl alcohol was added and heating was continued for another 2 hr. The cooled solution was diluted with ethyl brine, dried and evaporated. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 8.2 g of 1-(5-chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone as a yellow solid.

Part B: Preparation of 3-Chloro-6-(4-methoxyphenyl)methylamino-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 3.92 g (59.6 mmol) of cyclopropylacetylene in 100 mL of dry THF was added dropwise over 5 min, 33.0 mL (52.4 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to stir at 0° for 30 min after which time it was cooled to −40° and a solution of 8.20 g (23.85 mmol) of 1-(5-chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone in 20 mL of dry THF was added dropwise over 5 min. The reaction mixture was stirred at −40° for 2.0 h after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-20% ethyl acetate in hexanes) affording 6.0 g of the title compound as a solid.

Part C: 3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl1-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture ws poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers.

Part D: rel-(3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 1.13 g of 3-(2-bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 50 mL of acetonitrile was added 25 mL of water and 5.7 g of ceric ammonium nitrate. After 30 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (270 mg) was the title compound.

Part E: rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethen yl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-(3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C₁₇H₁₄NO₂F₃Cl (M+H)⁺: 354.0508. Found: 354.0487.

Example 42 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of trans-3-Chloro-6-(4-methoxyphenyl)methylamin-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol

To a solution of 1.23 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (from Example 41, Part B) in 12 mL of dry THF was added 15 mL of a 1M solution of lithium aluminum hydride in THF. The reaction mixture was stirred at ambient temperature for 3 days after which time it was quenched by the dropwise addition of 1.1 mL of concentrated aqueous ammonium hydroxide. This mixture was poured onto water and extracted with ether. The extracts were washed with brine, dried and evaporated to afford 1.15 g of the title compound as a pure oil.

Part B: trans-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 1.65 g of trans-3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethenyl-α-diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-33% ethyl acetate in hexanes) affording the title compound. A later eluting fraction (160 mg) proved to be uncyclized material, This was combined with 300 mg of cesium carbonate in 4 mL of DMF and stirred overnight at room temperature. The reaction mixture was poured onto water and extracted with ether. the organic layer was washed with brine, dried and evaporated to give when combined with the product obtained from the column chromatography 750 mg of the title compound as a mixture of diastereomers.

Part C: rel-(3S,5S)-trans-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2 (3H)-one

To a room temperature solution of 750 mg of trans-3-(2bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-l-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.

Part D: rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borohydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed.with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS: Calcd. for C₁₇H₁₆NO₂F₃Cl (M+H)⁺: 358.082166. Found: 358.081658.

Example 43 rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoramethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 71 mg of rel-(3S,5S)-7-chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 41) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and the filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 65 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 36 mg: mp 192-192.5°; HRMS: Calcd. for C₁₈H₁₄NO₂F₃Cl (M−H)⁻: 368.0665. Found: 368.0657.

Example 44 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 73 mg of rel-(3S,5S)-trans-7-chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 42) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and the filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 47 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 31 mg: mp 143-144°; HRMS: Calcd. for C₁₈H₁₆NO₂F₃Cl (M−H)⁻: 370.0822. Found: 370.0801.

Example 45 rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 41: mp 171-172°; HRMS: Calcd. for C₁₇H₁₃NO₂F₅ (M+H)⁺: 358.0866. Found: 358.0881.

Example 46 rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 45 in a manner similar to the procedure described in Example 43: mp 222-222.50; HRMS: Calcd. for C₁₈H₁₅NO₂F₅ (M+H)⁺: 373.1023. Found: 372.1013.

Example 47 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 41: Calcd. for C₁₇H₁₂NO₂F₄ (M−H)⁻: 338.0804. Found: 338.0815.

Example 48 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 184-185°; HRMS: Calcd. for C₁₆H₁₄NO₂F₄ (M+H)⁺: 328.0961. Found: 328.0955.

Example 49 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 186°; Anal. Calcd. for C₁₇H₁₅NO₂F₄: C, 59.83; H, 4,43; N, 4.10. Found: C, 59.56; H, 4.37; N, 4.02.

Example 50 rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title. compound can be prepared in a manner similar Calcd. for C₁₆H₁₆NO₂F₄ (M+H)⁺: 330.1117. Found: 330.1118.

Example 51 rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 148-149°; HRMS: Calcd. for C₁₇H₁₈₃NO₂F₄ (M+H)⁺: 344.1274. Found: 344.1265.

Example 52 rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 252-253°.

Example 53 rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 201-202°; HRMS: Calcd. for C₁₈H₁₇NO₄F₃ (M+): 367.1031. Found: 367.1041.

Example 54 rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described Example 29: mp 236-237°; HRMS: Calcd. for C₁₇H₁₇NO₄F₃ (M+H)⁺: 356.1110. Found: 356.1110.

Example 55 rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 188-190°; HRMS: Calcd. for C₁₈H₁₉NO₄F₃ (M+H)⁺: 370.1267. Found: 370.1269.

TABLE 1

Ex. # G R² R^(a) m.p. (° C.) Mass Spec  1 7-Cl C≡C-Et H 167-168  2 7-Cl (S)-C≡C-Et (S)-Ph 198-199 394.08  3 7-Cl C≡C-iPr H   183-183.5 332.07  4 (+) 7-Cl (S)-C≡C-iPr H 135-136  5 7-Cl trans-C═C-cycPr H 157-158 332.06  6 7-Cl trans-C═C-cycPr (S)-CH₃ 171-172 346.08  7 7-F C≡C-iPr H 172-173  8 7-F 3-methylbutyl H 320.13  9 7-Cl (S)-trans-C═C-2-furan (S)-CH₃   205-206.5 10 7-Cl trans-C═C-2-furan H 199-200 11 7-Cl (S)-C≡C-2-furan (S)-CH₃ 369.04 12 7-Cl butyl H 322.08 13 6,7-diF C≡C-iPr H 192.5-193.5 334.08 14a 7-Cl (S)-C≡C-cycPr (S)-CH₃ 191-92  14b 7-Cl (S)-C≡C-cycPr (R)-CH₃ 141 372.10 15 7-Cl (S)-C≡C-cycPr (S)-iPr 167 16 7-Cl C≡C-Ph H 190-191 17 7-Cl (S)-C≡C-iPr (S)-CH₃   181-182.8 18 7-Cl C≡C-cycPr H 199.5-200.5 19 7-Cl C≡C-iPr H 168-169 20 7-Cl trans-C═C-cycPr H 148-149 21 7-CH₃O C≡C-cycPr H 129-130 22 7-Cl (S)-C≡C-cycPr (S)-Et 180-181 23 7-Cl (S)-C≡C-cycPr (R)-Et 129-130 358.08 24 7-Cl C≡C-3-pyridyl H 219-221 367.05 25 7-Cl trans-C═C-3-pyridyl H 199-201 369.06 26 7-F trans-C═C-iPr H 145-156 27 6,7-F trans-C═C-iPr H 159-160 336.10 28 7-Cl (S)-C≡C-cycPr (S)-CH₃ 169-174 343.06 29 7-Cl (S)-trans-C═C-cycPr (S)-CH₃   147-147.5 360.10 30 7-Cl (S)-trans-C═C-cycPr (S)-Pr 165-167 374.11 31 7-Cl (S)-C≡C-3-furan (S)-CH₃ 214-215 32 7-Cl (S)-C≡C-3-furan (S)-Et 169-170 384.06 33 6,7-F (S)-C≡C-cycPr (S)-CH₃ 219-220 34 6,7-F (S)-C≡C-cycPr (S)-Et 180.4-181.4 35 6,7-F (S)-C≡C-cycPr (S)-CH₃ 192-193 348.10 36 (+) 7-Cl (S)-C≡C-cycPr (S)-CH₃ 145-146 37 7-Cl (S)-C≡C-cycPr H 135-136 38 7-Cl (S)-trans-C═C-cycPr (S)-Et   147-147.5 360.10 39 (+) 7-Cl (S)-trans-C═C-cycPr (S)-CH₃   175-175.5 40 (+) 7-Cl (S)-trans-C═C-cycPr (S)-Et 163-164 41 7-Cl (S)-C≡C-cycPr (S)-CH═CH₂ 354.05 42 7-Cl (S)-trans-C═C-cycPr (S)-CH═CH₂ 165.5-166.5 358.08 43 7-Cl (S)-C≡C-cycPr (S)-cycPr   192-192.5 368.07 44 7-Cl (S)-trans-C═C-cycPr (S)-cycPr 143-144 370.08 45 6,7-F (S)-C≡C-cycPr (S)-CH═CH₂ 171-172 358.09 46 6,7-F (S)-C≡C-cycPr (S)-cycPr   222-222.5 372.10 47 7-F (S)-C≡C-cycPr (S)-CH═CH₂ 338.08 48 7-F (S)-C≡C-cycPr (S)-CH₃ 184-185 328.10 49 7-F (S)-C≡C-cycPr (S)-Et 186 50 7-F (S)-trans-C═C-cycPr (S)-CH₃ 180-182 330.11 51 7-F (S)-trans-C═C-cycPr (S)-Et 148-149 344.13 52 6,7-(CH₂)₂O (S)-C≡C-cycPr (S)-CH₃ 252-252 53 6,7-(CH₂)₂O (S)-C≡C-cycPr (S)-Et 201-202 367.10 54 6,7-(CH₂)₂O (S)-trans-C═C-cycPr (S)-CH₃ 236-237 356.11 55 6,7-(CH₂)₂O (S)-trans-C═C-cycPr (S)-Et 188-190 370.13 *Unless otherwise noted, stereochemistry is (+/−).

Tables 2 and 3 show representative compounds of the present invention. Each formula shown at the start of Table 2 and 3 is intended to be paired with each entry in the table which follows.

TABLE 2

a

b

c

d

e

f

g

h

i Ex. # G R¹ R² 201 6-Cl CF₃ n-butyl 202 6-Cl CF₃ C≡C—Et 203 6-Cl CF₃ C≡C-iPr 204 6-Cl CF₃ C≡C-cycPr 205 6-Cl CF₃ C≡C-2-pyridy1 206 6-Cl CF₃ C≡C-3-pyridyl 207 6-Cl CF₃ C≡C-2-furanyl 208 6-Cl CF₃ C≡C-3-furanyl 209 6-Cl CF₃ C≡C-2-thienyl 210 6-Cl CF₃ C≡C-3-thienyl 211 6-Cl CF₃ CH═CH—Et 212 6-Cl CF₃ CH═CH-iPr 213 6-Cl CF₃ CH═CH-cycPr 214 6-Cl CF₃ CH═CH-2-pyridyl 215 6-Cl CF₃ CH═CH-3-pyridyl 216 6-Cl CF₃ CH═CH-2-furanyl 217 6-Cl CF₃ CH═CH-3-furanyl 218 6-Cl CF₃ CH═CH-2-thienyl 219 6-Cl CF₃ CH═CH-3-thienyl 220 6-Cl CF₃ CH₂—C≡C-cycPr 221 6-Cl CF₃ CH₂—C≡C-2- furanyl 222 6-Cl CF₃ CH₂CH═CH-cycPr 223 6-Cl CF₃ CH₂CH═CH-2- furanyl 224 6-Cl CF₃ CH═CHCH₂-cycPr 225 6-Cl CF₃ CH═CHCH₂-2- furanyl 226 7-Cl CF₃ n-butyl 227 7-Cl CF₃ C≡C—Et 228 7-Cl CF₃ C≡C-iPr 229 7-Cl CF₃ C≡C-cycPr 230 7-Cl CF₃ C≡C-2-pyridyl 231 7-Cl CF₃ C≡C-3-pyridyl 232 7-Cl CF₃ C≡C-2-furanyl 233 7-Cl CF₃ C≡C-3-furanyl 234 7-Cl CF₃ C≡C-2-thienyl 235 7-Cl CF₃ C≡C-3-thienyl 236 7-Cl CF₃ CH═CH—Et 237 7-Cl CF₃ CH═CH-iPr 238 7-Cl CF₃ CH═CH-cycPr 239 7-Cl CF₃ CH═CH-2-pyridyl 240 7-Cl CF₃ CH═CH-3-pyridyl 241 7-Cl CF₃ CH═CH-2-furanyl 242 7-Cl CF₃ CH═CH-3-furanyl 243 7-Cl CF₃ CH═CH-2-thienyl 244 7-Cl CF₃ CH═CH-3-thienyl 245 7-Cl CF₃ CH₂—C≡C-cycPr 246 7-Cl CF₃ CH₂—C≡C-2- furanyl 247 7-Cl CF₃ CH₂CH═CH-cycPr 248 7-Cl CF₃ CH₂CH═CH-2- furanyl 249 7-Cl CF₃ CH═CHCH₂-cycPr 250 7-Cl CF₃ CH═CHCH₂-2- furanyl 251 6-F CF₃ n-butyl 252 6-F CF₃ C≡C—Et 253 6-F CF₃ C≡C-iPr 254 6-F CF₃ C≡C-cycPr 255 6-F CF₃ C≡C-2-pyridyl 256 6-F CF₃ C≡C-3-pyridyl 257 6-F CF₃ C≡C-2-furanyl 258 6-F CF₃ C≡C-3-furanyl 259 6-F CF₃ C≡C-2-thienyl 260 6-F CF₃ C≡C-3-thienyl 261 6-F CF₃ CH═CH—Et 262 6-F CF₃ CH═CH-iPr 263 6-F CF₃ CH═CH-cycPr 264 6-F CF₃ CH═CH-2-pyridyl 265 6-F CF₃ CH═CH-3-pyridyl 266 6-F CF₃ CH═CH-2-furanyl 267 6-F CF₃ CH═CH-3-furanyl 268 6-F CF₃ CH═CH-2-thienyl 269 6-F CF₃ CH═CH-3-thienyl 270 6-F CF₃ CH₂—C≡C-cycPr 271 6-F CF₃ CH₂—C≡C-2- furanyl 272 6-F CF₃ CH₂CH═CH-cycPr 273 6-F CF₃ CH₂CH═CH-2- furanyl 274 6-F CF₃ CH═CHCH₂-cycPr 275 6-F CF₃ CH═CHCH₂-2- furanyl 276 7-F CF₃ n-butyl 277 7-F CF₃ C≡C—Et 278 7-F CF₃ C≡C-iPr 279 7-F CF₃ C≡C-cycPr 280 7-F CF₃ C≡C-2-pyridyl 281 7-F CF₃ C≡C-3-pyridyl 282 7-F CF₃ C≡C-2-furanyl 283 7-F CF₃ C≡C-3-furanyl 284 7-F CF₃ C≡C-2-thieny1 285 7-F CF₃ C≡C-3-thieny1 286 7-F CF₃ CH═CH—Et 287 7-F CF₃ CH═CH-iPr 288 7-F CF₃ CH═CH-cycPr 289 7-F CF₃ CH═CH-2-pyridyl 290 7-F CF₃ CH═CH-3-pyridyl 291 7-F CF₃ CH═CH-2-furanyl 292 7-F CF₃ CH═CH-3-furanyl 293 7-F CF₃ CH═CH-2-thienyl 294 7-F CF₃ CH═CH-3-thienyl 295 7-F CF₃ CH₂—C≡C-cycPr 296 7-F CF₃ CH₂—C≡C-2- furanyl 297 7-F CF₃ CH₂CH═CH-cycPr 298 7-F CF₃ CH₂CH═CH-2- furanyl 299 7-F CF₃ CH═CHCH₂-cycPr 300 7-F CF₃ CH═CHCH₂-2- furanyl 301 6,7-diCl CF₃ n-butyl 302 6,7-diCl CF₃ C≡C—Et 303 6,7-diCl CF₃ C≡C-iPr 304 6,7-diCl CF₃ C≡C-cycPr 305 6,7-diCl CF₃ C≡C-2-pyridyl 306 6,7-diCl CF₃ C≡C-3-pyridyl 307 6,7-diCl CF₃ C≡C-2-furanyl 308 6,7-diCl CF₃ C≡C-3-furanyl 309 6,7-diCl CF₃ C≡C-2-thienyl 310 6,7-diCl CF₃ C≡C-3-thienyl 311 6,7-diCl CF₃ CH═CH—Et 312 6,7-diCl CF₃ CH═CH-iPr 313 6,7-diCl CF₃ CH═CH-cycPr 314 6,7-diCl CF₃ CH═CH-2-pyridyl 315 6,7-diCl CF₃ CH═CH-3-pyridyl 316 6,7-diCl CF₃ CH═CH-2-furanyl 317 6,7-diCl CF₃ CH═CH-3-furanyl 318 6,7-diCl CF₃ CH═CH-2-thienyl 319 6,7-diCl CF₃ CH═CH-3-thienyl 320 6,7-diCl CF₃ CH₂—C≡C-cycPr 321 6,7-diCl CF₃ CH₂—C≡C-2- furanyl 322 6,7-diCl CF₃ CH₂CH═CH-cycPr 323 6,7-diCl CF₃ CH₂CH═CH-2- furanyl 324 6,7-diCl CF₃ CH═CHCH₂-cycPr 325 6,7-diCl CF₃ CH═CHCH₂-2- furanyl 326 6,7-diF CF₃ n-butyl 327 6,7-diF CF₃ C≡C—Et 328 6,7-diF CF₃ C≡C-iPr 329 6,7-diF CF₃ C≡C-cycPr 330 6,7-diF CF₃ C≡C-2-pyridyl 331 6,7-diF CF₃ C≡C-3-pyridyl 332 6,7-diF CF₃ C≡C-2-furanyl 333 6,7-diF CF₃ C≡C-3-furanyl 334 6,7-diF CF₃ C≡C-2-thienyl 335 6,7-diF CF₃ C≡C-3-thienyl 336 6,7-diF CF₃ CH═CH—Et 337 6,7-diF CF₃ CH═CH-iPr 338 6,7-diF CF₃ CH═CH-cycPr 339 6,7-diF CF₃ CH═CH-2-pyridyl 340 6,7-diF CF₃ CH═CH-3-pyridyl 341 6,7-diF CF₃ CH═CH-2-furanyl 342 6,7-diF CF₃ CH═CH-3-furanyl 343 6,7-diF CF₃ CH═CH-2-thienyl 344 6,7-diF CF₃ CH═CH-3-thienyl 345 6,7-diF CF₃ CH₂—C≡C-cycPr 346 6,7-diF CF₃ CH₂—C≡C-2- furanyl 347 6,7-diF CF₃ CH₂CH═CH-cycPr 348 6,7-diF CF₃ CH₂CH═CH-2- furanyl 349 6,7-diF CF₃ CH═CHCH₂-cycPr 350 6,7-diF CF₃ CH═CHCH₂-2- furanyl 351 6-Cl, 7-F CF₃ n-butyl 352 6-Cl, 7-F CF₃ C≡C—Et 353 6-Cl, 7-F CF₃ C≡C-iPr 354 6-Cl, 7-F CF₃ C≡C-cycPr 355 6-Cl, 7-F CF₃ C≡C-2-pyridyl 356 6-Cl, 7-F CF₃ C≡C-3-pyridyl 357 6-Cl, 7-F CF₃ C≡C-2-furanyl 358 6-Cl, 7-F CF₃ C≡C-3-furanyl 359 6-Cl, 7-F CF₃ C≡C-2-thienyl 360 6-Cl, 7-F CF₃ C≡C-3-thienyl 361 6-Cl, 7-F CF₃ CH═CH—Et 362 6-Cl, 7-F CF₃ CH═CH-iPr 363 6-Cl, 7-F CF₃ CH═CH-cycPr 364 6-Cl, 7-F CF₃ CH═CH-2-pyridyl 365 6-Cl, 7-F CF₃ CH═CH-3-pyridyl 366 6-Cl, 7-F CF₃ CH═CH-2-furanyl 367 6-Cl, 7-F CF₃ CH═CH-3-furanyl 368 6-Cl, 7-F CF₃ CH═CH-2-thienyl 369 6-Cl, 7-F CF₃ CH═CH-3-thienyl 370 6-Cl, 7-F CF₃ CH₂—C≡C-cycPr 371 6-Cl, 7-F CF₃ CH₂—C≡C-2- furanyl 372 6-Cl, 7-F CF₃ CH₂CH═CH-cycPr 373 6-Cl, 7-F CF₃ CH₂CH═CH-2- furanyl 374 6-Cl, 7-F CF₃ CH═CHCH₂-cycPr 375 6-Cl, 7-F CF₃ CH═CHCH₂-2- furanyl 376 6-F, 7-Cl CF₃ n-butyl 377 6-F, 7-Cl CF₃ C≡C—Et 378 6-F, 7-Cl CF₃ C≡C-iPr 379 6-F, 7-Cl CF₃ C≡C-cycPr 380 6-F, 7-Cl CF₃ C≡C-2-pyridyl 381. 6-F, 7-Cl CF₃ C≡C-3-pyridyl 382 6-F, 7-Cl CF₃ C≡C-2-furanyl 383 6-F, 7-Cl CF₃ C≡C-3-furanyl 384 6-F, 7-Cl CF₃ C≡C-2-thienyl 385 6-F, 7-Cl CF₃ C≡C-3-thienyl 386 6-F, 7-Cl CF₃ CH═CH—Et 387 6-F, 7-Cl CF₃ CH═CH-iPr 388 6-F, 7-Cl CF₃ CH═CH-cycPr 389 6-F, 7-Cl CF₃ CH═CH-2-pyridyl 390 6-F, 7-Cl CF₃ CH═CH-3-pyridyl 391 6-F, 7-Cl CF₃ CH═CH-2-furanyl 392 6-F, 7-Cl CF₃ CH═CH-3-furanyl 393 6-F, 7-Cl CF₃ CH═CH-2-thienyl 394 6-F, 7-Cl CF₃ CH═CH-3-thienyl 395 6-F, 7-Cl CF₃ CH₂—C≡C-cycPr 396 6-F, 7-Cl CF₃ CH₂—C≡C-2- furanyl 397 6-F, 7-Cl CF₃ CH₂CH═CH-cycPr 398 6-F, 7-Cl CF₃ CH₂CH═CH-2- furanyl 399 6-F, 7-Cl CF₃ CH═CHCH₂-cycPr 400 6-F, 7-Cl CF₃ CH═CHCH₂-2- furanyl 401 7-CH₃ CF₃ n-butyl 402 7-CH₃ CF₃ C≡C—Et 403 7-CH₃ CF₃ C≡C-iPr 404 7-CH₃ CF₃ C≡C-cycPr 405 7-CH₃ CF₃ C≡C-2-pyridyl 406 7-CH₃ CF₃ C≡C-3-pyridyl 407 7-CH₃ CF₃ C≡C-2-furanyl 408 7-CH₃ CF₃ C≡C-3-furanyl 409 7-CH₃ CF₃ C≡C-2-thienyl 410 7-CH₃ CF₃ C≡C-3-thienyl 411 7-CH₃ CF₃ CH═CH—Et 412 7-CH₃ CF₃ CH═CH-iPr 413 7-CH₃ CF₃ CH═CH-cycPr 414 7-CH₃ CF₃ CH═CH-2-pyridyl 415 7-CH₃ CF₃ CH═CH-3-pyridyl 416 7-CH₃ CF₃ CH═CH-2-furanyl 417 7-CH₃ CF₃ CH═CH-3-furanyl 418 7-CH₃ CF₃ CH═CH-2-thienyl 419 7-CH₃ CF₃ CH═CH-3-thienyl 420 7-CH₃ CF₃ CH₂—C≡C-cycPr 421 7-CH₃ CF₃ CH₂—C≡C-2- furanyl 422 7-CH₃ CF₃ CH₂CH═CH-cycPr 423 7-CH₃ CF₃ CH₂CH═CH-2- furanyl 424 7-CH₃ CF₃ CH═CHCH₂-cycPr 425 7-CH₃ CF₃ CH═CHCH₂-2- furanyl 426 7-OCH₃ CF₃ n-butyl 427 7-OCH₃ CF₃ C≡C—Et 428 7-OCH₃ CF₃ C≡C-iPr 429 7-OCH₃ CF₃ C≡C-cycPr 430 7-OCH₃ CF₃ C≡C-2-pyridyl 431 7-OCH₃ CF₃ C≡C-3-pyridyl 432 7-OCH₃ CF₃ C≡C-2-furanyl 433 7-OCH₃ CF₃ C≡C-3-furanyl 434 7-OCH₃ CF₃ C≡C-2-thienyl 435 7-OCH₃ CF₃ C≡C-3-thienyl 436 7-OCH₃ CF₃ CH═CH—Et 437 7-OCH₃ CF₃ CH═CH-iPr 438 7-OCH₃ CF₃ CH═CH-cycPr 439 7-OCH₃ CF₃ CH═CH-2-pyridyl 440 7-OCH₃ CF₃ CH═CH-3-pyridyl 441 7-OCH₃ CF₃ CH═CH-2-furanyl 442 7-OCH₃ CF₃ CH═CH-3-furanyl 443 7-OCH₃ CF₃ CH═CH-2-thienyl 444 7-OCH₃ CF₃ CH═CH-3-thienyl 445 7-OCH₃ CF₃ CH₂—C≡C-cycPr 446 7-OCH₃ CF₃ CH₂—C≡C-2- furanyl 447 7-OCH₃ CF₃ CH₂CH═CH-cycPr 448 7-OCH₃ CF₃ CH₂CH═CH-2- furanyl 449 7-OCH₃ CF₃ CH═CHCH₂-cycPr 450 7-OCH₃ CF₃ CH═CHCH₂-2- furanyl 451 7-pyrazol- CF₃ n-butyl 6-yl 452 7-pyrazol- CF₃ C≡C—Et 6-yl 453 7-pyrazol- CF₃ C≡C-iPr 6-yl 454 7-pyrazol- CF₃ C≡C-cycPr 6-yl 455 7-pyrazol- CF₃ C≡C-2-pyridyl 6-yl 456 7-pyrazol- CF₃ C≡C-3-pyridyl 6-yl 457 7-pyrazol- CF₃ C≡C-2-furanyl 6-yl 458 7-pyrazol- CF₃ C≡C-3-furanyl 6-yl 459 7-pyrazol- CF₃ C≡C-2-thienyl 6-yl 460 7-pyrazol- CF₃ C≡C-3-thienyl 6-yl 461 7-pyrazol- CF₃ CH═CH—Et 6-yl 462 7-pyrazol- CF₃ CH═CH-iPr 6-yl 463 7-pyrazol- CF₃ CH═CH-cycPr 6-yl 464 7-pyrazol- CF₃ CH═CH-2-pyridyl 6-yl 465 7-pyrazol- CF₃ CH═CH-3-pyridyl 6-yl 466 7-pyrazol- CF₃ CH═CH-2-furanyl 6-yl 467 7-pyrazol- CF₃ CH═CH-3-furanyl 6-yl 468 7-pyrazol- CF₃ CH═CH-2-thienyl 6-yl 469 7-pyrazol- CF₃ CH═CH-3-thienyl 6-yl 470 7-pyrazol- CF₃ CH₂—C≡C-cycPr 6-yl 471 7-pyrazol- CF₃ CH₂—C≡C-2- 6-yl furanyl 472 7-pyrazol- CF₃ CH₂CH═CH-cycPr 6-yl 473 7-pyrazol- CF₃ CH₂CH═CH-2- 6-yl furanyl 474 7-pyrazol- CF₃ CH═CHCH₂-cycPr 6-yl 475 7-pyrazol- CF₃ CH═CHCH₂-2- 6-yl furanyl 476 6,7-OCH₂O— CF₃ n-butyl 477 6,7-OCH₂O— CF₃ C≡C—Et 478 6,7-OCH₂O— CF₃ C≡C-iPr 479 6,7-OCH₂O— CF₃ C≡C-cycPr 480 6,7-OCH₂O— CF₃ C≡C-2-pyridyl 481 6,7-OCH₂O— CF₃ C≡C-3-pyridyl 482 6,7-OCH₂O— CF₃ C≡C-2-furanyl 483 6,7-OCH₂O— CF₃ C≡C-3-furanyl 484 6,7-OCH₂O— CF₃ C≡C-2-thienyl 485 6,7-OCH₂O— CF₃ C≡C-3-thienyl 486 6,7-OCH₂O— CF₃ CH═CH—Et 487 6,7-OCH₂O— CF₃ CH═CH-iPr 488 6,7-OCH₂O— CF₃ CH═CH-cycPr 489 6,7-OCH₂O— CF₃ CH═CH-2-pyridyl 490 6,7-OCH₂O— CF₃ CH═CH-3-pyridyl 491 6,7-OCH₂O— CF₃ CH═CH-2-furanyl 492 6,7-OCH₂O— CF₃ CH═CH-3-furanyl 493 6,7-OCH₂O— CF₃ CH═CH-2-thienyl 494 6,7-OCH₂O— CF₃ CH═CH-3-thienyl 495 6,7-OCH₂O— CF₃ CH₂—C≡C-cycPr 496 6,7-OCH₂O— CF₃ CH₂—C≡C-2- furanyl 497 6,7-OCH₂O— CF₃ CH₂CH═CH-cycPr 498 6,7-OCH₂O— CF₃ CH₂CH═CH-2- furanyl 499 6,7-OCH₂O— CF₃ CH═CHCH₂-cycPr 500 6,7-OCH₂O— CF₃ CH═CHCH₂-2- furanyl 501 7-CONH₂ CF₃ n-butyl 502 7-CONH₂ CF₃ C≡C—Et 503 7-CONH₂ CF₃ C≡C-iPr 504 7-CONH₂ CF₃ C≡C-cycPr 505 7-CONH₂ CF₃ C≡C-2-pyridyl 506 7-CONH₂ CF₃ C≡C-3-pyridyl 507 7-CONH₂ CF₃ C≡C-2-furanyl 508 7-CONH₂ CF₃ C≡C-3-furanyl 509 7-CONH₂ CF₃ C≡C-2-thienyl 510 7-CONH₂ CF₃ C≡C-3-thienyl 511 7-CONH₂ CF₃ CH═CH—Et 512 7-CONH₂ CF₃ CH═CH-iPr 513 7-CONH₂ CF₃ CH═CH-cycPr 514 7-CONH₂ CF₃ CH═CH-2-pyridyl 515 7-CONH₂ CF₃ CH═CH-3-pyridyl 516 7-CONH₂ CF₃ CH═CH-2-furanyl 517 7-CONH₂ CF₃ CH═CH-3-furanyl 518 7-CONH₂ CF₃ CH═CH-2-thienyl 519 7-CONH₂ CF₃ CH═CH-3-thienyl 520 7-CONH₂ CF₃ CH₂—C≡C-cycPr 521 7-CONH₂ CF₃ CH₂—C≡C-2- furanyl 522 7-CONH₂ CF₃ CH₂CH═CH-cycPr 523 7-CONH₂ CF₃ CH₂CH═CH-2- furanyl 524 7-CONH₂ CF₃ CH═CHCH₂-cycPr 525 7-CONH₂ CF₃ CH═CHCH₂-2- furanyl 526 6-Cl C₂F₅ n-butyl 527 6-Cl C₂F₅ C≡C—Et 528 6-Cl C₂F₅ C≡C-iPr 529 6-Cl C₂F₅ C≡C-cycPr 530 6-Cl C₂F₅ C≡C-2-pyridy1 531 6-Cl C₂F₅ C≡C-3-pyridyl 532 6-Cl C₂F₅ C≡C-2-furanyl 533 6-Cl C₂F₅ C≡C-3-furanyl 534 6-Cl C₂F₅ C≡C-2-thienyl 535 6-Cl C₂F₅ C≡C-3-thienyl 536 6-Cl C₂F₅ CH═CH—Et 537 6-Cl C₂F₅ CH═CH-iPr 538 6-Cl C₂F₅ CH═CH-cycPr 539 6-Cl C₂F₅ CH═CH-2-pyridyl 540 6-Cl C₂F₅ CH═CH-3-pyridyl 541 6-Cl C₂F₅ CH═CH-2-furanyl 542 6-Cl C₂F₅ CH═CH-3-furanyl 543 6-Cl C₂F₅ CH═CH-2-thienyl 544 6-Cl C₂F₅ CH═CH-3-thienyl 545 6-Cl C₂F₅ CH₂—C≡C-cycPr 546 6-Cl C₂F₅ CH₂—C≡C-2- furanyl 547 6-Cl C₂F₅ CH₂CH═CH-cycPr 548 6-Cl C₂F₅ CH₂CH═CH-2- furanyl 549 6-Cl C₂F₅ CH═CHCH₂-cycPr 550 6-Cl C₂F₅ CH═CHCH₂-2- furanyl 551 7-Cl C₂F₅ n-butyl 552 7-Cl C₂F₅ C≡C—Et 553 7-Cl C₂F₅ C≡C-iPr 554 7-Cl C₂F₅ C≡C-cycPr 555 7-Cl C₂F₅ C≡C-2-pyridyl 556 7-Cl C₂F₅ C≡C-3-pyridyl 557 7-Cl C₂F₅ C≡C-2-furanyl 558 7-Cl C₂F₅ C≡C-3-furanyl 559 7-Cl C₂F₅ C≡C-2-thienyl 560 7-Cl C₂F₅ C≡C-3-thienyl 561 7-Cl C₂F₅ CH═CH—Et 562 7-Cl C₂F₅ CH═CH-iPr 563 7-Cl C₂F₅ CH═CH-cycPr 564 7-Cl C₂F₅ CH═CH-2-pyridyl 565 7-Cl C₂F₅ CH═CH-3-pyridyl 566 7-Cl C₂F₅ CH═CH-2-furanyl 567 7-Cl C₂F₅ CH═CH-3-furanyl 568 7-Cl C₂F₅ CH═CH-2-thienyl 569 7-Cl C₂F₅ CH═CH-3-thienyl 570 7-Cl C₂F₅ CH₂—C≡C-cycPr 571 7-Cl C₂F₅ CH₂—C≡C-2- furanyl 572 7-Cl C₂F₅ CH₂CH═CH-cycPr 573 7-Cl C₂F₅ CH₂CH═CH-2- furanyl 574 7-Cl C₂F₅ CH═CHCH₂-cycPr 575 7-Cl C₂F₅ CH═CHCH₂-2- furanyl 576 6-F C₂F₅ n-butyl 577 6-F C₂F₅ C≡C—Et 578 6-F C₂F₅ C≡C-iPr 579 6-F C₂F₅ C≡C-cycPr 580 6-F C₂F₅ C≡C-2-pyridyl 581 6-F C₂F₅ C≡C-3-pyridyl 582 6-F C₂F₅ C≡C-2-furanyl 583 6-F C₂F₅ C≡C-3-furanyl 584 6-F C₂F₅ C≡C-2-thienyl 585 6-F C₂F₅ C≡C-3-thienyl 586 6-F C₂F₅ CH═CH—Et 587 6-F C₂F₅ CH═CH-iPr 588 6-F C₂F₅ CH═CH-cycPr 589 6-F C₂F₅ CH═CH-2-pyridyl 590 6-F C₂F₅ CH═CH-3-pyridyl 591 6-F C₂F₅ CH═CH-2-furanyl 592 6-F C₂F₅ CH═CH-3-furanyl 593 6-F C₂F₅ CH═CH-2-thienyl 594 6-F C₂F₅ CH═CH-3-thienyl 595 6-F C₂F₅ CH₂—C≡C-cycPr 596 6-F C₂F₅ CH₂—C≡C-2- furanyl 597 6-F C₂F₅ CH₂CH═CH-cycPr 598 6-F C₂F₅ CH₂CH═CH-2- furanyl 599 6-F C₂F₅ CH═CHCH₂-cycPr 600 6-F C₂F₅ CH═CHCH₂-2- furanyl 601 7-F C₂F₅ n-butyl 602 7-F C₂F₅ C≡C—Et 603 7-F C₂F₅ C≡C-iPr 604 7-F C₂F₅ C≡C-cycPr 605 7-F C₂F₅ C≡C-2-pyridyl 606 7-F C₂F₅ C≡C-3-pyridyl 607 7-F C₂F₅ C≡C-2-furanyl 608 7-F C₂F₅ C≡C-3-furanyl 609 7-F C₂F₅ C≡C-2-thienyl 610 7-F C₂F₅ C≡C-3-thienyl 611 7-F C₂F₅ CH═CH—Et 612 7-F C₂F₅ CH═CH-iPr 613 7-F C₂F₅ CH═CH-cycPr 614 7-F C₂F₅ CH═CH-2-pyridyl 615 7-F C₂F₅ CH═CH-3-pyridyl 616 7-F C₂F₅ CH═CH-2-furanyl 617 7-F C₂F₅ CH═CH-3-furanyl 618 7-F C₂F₅ CH═CH-2-thienyl 619 7-F C₂F₅ CH═CH-3-thienyl 620 7-F C₂F₅ CH₂—C≡C-cycPr 621 7-F C₂F₅ CH₂—C≡C-2- furanyl 622 7-F C₂F₅ CH₂CH═CH-cycPr 623 7-F C₂F₅ CH₂CH═CH-2- furanyl 624 7-F C₂F₅ CH═CHCH₂-cycPr 625 7-F C₂F₅ CH═CHCH₂-2- furanyl 626 6,7-diCl C₂F₅ n-butyl 627 6,7-diCl C₂F₅ C≡C—Et 628 6,7-diCl C₂F₅ C≡C-iPr 629 6,7-diCl C₂F₅ C≡C-cycPr 630 6,7-diCl C₂F₅ C≡C-2-pyridyl 631 6,7-diCl C₂F₅ C≡C-3-pyridyl 632 6,7-diCl C₂F₅ C≡C-2-furanyl 633 6,7-diCl C₂F₅ C≡C-3-furanyl 634 6,7-diCl C₂F₅ C≡C-2-thienyl 635 6,7-diCl C₂F₅ C≡C-3-thieny1 636 6,7-diCl C₂F₅ CH═CH—Et 637 6,7-diCl C₂F₅ CH═CH-iPr 638 6,7-diCl C₂F₅ CH═CH-cycPr 639 6,7-diCl C₂F₅ CH═CH-2-pyridyl 640 6,7-diCl C₂F₅ CH═CH-3-pyridyl 641 6,7-diCl C₂F₅ CH═CH-2-furanyl 642 6,7-diCl C₂F₅ CH═CH-3-furanyl 643 6,7-diCl C₂F₅ CH═CH-2-thienyl 644 6,7-diCl C₂F₅ CH═CH-3-thienyl 645 6,7-diCl C₂F₅ CH₂—C≡C-cycPr 646 6,7-diCl C₂F₅ CH₂—C≡C-2- furanyl 647 6,7-diCl C₂F₅ CH₂CH═CH-cycPr 648 6,7-diCl C₂F₅ CH₂CH═CH-2- furanyl 649 6,7-diCl C₂F₅ CH═CHCH₂-cycPr 650 6,7-diCl C₂F₅ CH═CHCH₂-2- furanyl 651 6,7-diF C₂F₅ n-butyl 652 6,7-diF C₂F₅ C≡C—Et 653 6,7-diF C₂F₅ C≡C-iPr 654 6,7-diF C₂F₅ C≡C-cycPr 655 6,7-diF C₂F₅ C≡C-2-pyridyl 656 6,7-diF C₂F₅ C≡C-3-pyridyl 657 6,7-diF C₂F₅ C≡C-2-furanyl 658 6,7-diF C₂F₅ C≡C-3-furanyl 659 6,7-diF C₂F₅ C≡C-2-thienyl 660 6,7-diF C₂F₅ C≡C-3-thienyl 661 6,7-diF C₂F₅ CH═CH—Et 662 6,7-diF C₂F₅ CH═CH-iPr 663 6,7-diF C₂F₅ CH═CH-cycPr 664 6,7-diF C₂F₅ CH═CH-2-pyridyl 665 6,7-diF C₂F₅ CH═CH-3-pyridyl 666 6,7-diF C₂F₅ CH═CH-2-furanyl 667 6,7-diF C₂F₅ CH═CH-3-furanyl 668 6,7-diF C₂F₅ CH═CH-2-thienyl 669 6,7-diF C₂F₅ CH═CH-3-thienyl 670 6,7-diF C₂F₅ CH₂—C≡C-cycPr 671 6,7-diF C₂F₅ CH₂—C≡C-2- furanyl 672 6,7-diF C₂F₅ CH₂CH═CH-cycPr 673 6,7-diF C₂F₅ CH₂CH═CH-2- furanyl 674 6,7-diF C₂F₅ CH═CHCH₂-cycPr 675 6,7-diF C₂F₅ CH═CHCH₂-2- furanyl 676 6-Cl, 7-F C₂F₅ n-butyl 677 6-Cl, 7-F C₂F₅ C≡C—Et 678 6-Cl, 7-F C₂F₅ C≡C-iPr 679 6-Cl, 7-F C₂F₅ C≡C-cycPr 680 6-Cl, 7-F C₂F₅ C≡C-2-pyridyl 681 6-Cl, 7-F C₂F₅ C≡C-3-pyridyl 682 6-Cl, 7-F C₂F₅ C≡C-2-furanyl 683 6-Cl, 7-F C₂F₅ C≡C-3-furanyl 684 6-Cl, 7-F C₂F₅ C≡C-2-thienyl 685 6-Cl, 7-F C₂F₅ C≡C-3-thienyl 686 6-Cl, 7-F C₂F₅ CH═CH—Et 687 6-Cl, 7-F C₂F₅ CH═CH-iPr 688 6-Cl, 7-F C₂F₅ CH═CH-cycPr 689 6-Cl, 7-F C₂F₅ CH═CH-2-pyridyl 690 6-Cl, 7-F C₂F₅ CH═CH-3-pyridyl 691 6-Cl, 7-F C₂F₅ CH═CH-2-furanyl 692 6-Cl, 7-F C₂F₅ CH═CH-3-furanyl 693 6-Cl, 7-F C₂F₅ CH═CH-2-thienyl 694 6-Cl, 7-F C₂F₅ CH═CH-3-thienyl 695 6-Cl, 7-F C₂F₅ CH₂—C≡C-cycPr 696 6-Cl, 7-F C₂F₅ CH₂—C≡C-2- furanyl 697 6-Cl, 7-F C₂F₅ CH₂CH═CH-cycPr 698 6-Cl, 7-F C₂F₅ CH₂CH═CH-2- furanyl 699 6-Cl, 7-F C₂F₅ CH═CHCH₂-cycPr 700 6-Cl, 7-F C₂F₅ CH═CHCH₂-2- furanyl 701 6-F, 7-Cl C₂F₅ n-butyl 702 6-F, 7-Cl C₂F₅ C≡C—Et 703 6-F, 7-Cl C₂F₅ C≡C-iPr 704 6-F, 7-Cl C₂F₅ C≡C-cycPr 705 6-F, 7-Cl C₂F₅ C≡C-2-pyridyl 706 6-F, 7-Cl C₂F₅ C≡C-3-pyridyl 707 6-F, 7-Cl C₂F₅ C≡C-2-furanyl 708 6-F, 7-Cl C₂F₅ C≡C-3-furanyl 709 6-F, 7-Cl C₂F₅ C≡C-2-thienyl 710 6-F, 7-Cl C₂F₅ C≡C-3-thienyl 711 6-F, 7-Cl C₂F₅ CH═CH—Et 712 6-F, 7-Cl C₂F₅ CH═CH-iPr 713 6-F, 7-Cl C₂F₅ CH═CH-cycPr 714 6-F, 7-Cl C₂F₅ CH═CH-2-pyridyl 715 6-F, 7-Cl C₂F₅ CH═CH-3-pyridyl 716 6-F, 7-Cl C₂F₅ CH═CH-2-furanyl 717 6-F, 7-Cl C₂F₅ CH═CH-3-furanyl 718 6-F, 7-Cl C₂F₅ CH═CH-2-thienyl 719 6-F, 7-Cl C₂F₅ CH═CH-3-thienyl 720 6-F, 7-Cl C₂F₅ CH₂—C≡C-cycPr 721 6-F, 7-Cl C₂F₅ CH₂—C≡C-2- furanyl 722 6-F, 7-Cl C₂F₅ CH₂CH═CH-cycPr 723 6-F, 7-Cl C₂F₅ CH₂CH═CH-2- furanyl 724 6-F, 7-Cl C₂F₅ CH═CHCH₂-cycPr 725 6-F, 7-Cl C₂F₅ CH═CHCH₂-2- furanyl 726 7-CH₃ C₂F₅ n-butyl 727 7-CH₃ C₂F₅ C≡C—Et 728 7-CH₃ C₂F₅ C≡C-iPr 729 7-CH₃ C₂F₅ C≡C-cycPr 730 7-CH₃ C₂F₅ C≡C-2-pyridyl 731 7-CH₃ C₂F₅ C≡C-3-pyridyl 732 7-CH₃ C₂F₅ C≡C-2-furanyl 733 7-CH₃ C₂F₅ C≡C-3-furanyl 734 7-CH₃ C₂F₅ C≡C-2-thienyl 735 7-CH₃ C₂F₅ C≡C-3-thienyl 736 7-CH₃ C₂F₅ CH═CH—Et 737 7-CH₃ C₂F₅ CH═CH-iPr 738 7-CH₃ C₂F₅ CH═CH-cycPr 739 7-CH₃ C₂F₅ CH═CH-2-pyridyl 740 7-CH₃ C₂F₅ CH═CH-3-pyridyl 741 7-CH₃ C₂F₅ CH═CH-2-furanyl 742 7-CH₃ C₂F₅ CH═CH-3-furanyl 743 7-CH₃ C₂F₅ CH═CH-2-thienyl 744 7-CH₃ C₂F₅ CH═CH-3-thienyl 745 7-CH₃ C₂F₅ CH₂—C≡C-cycPr 746 7-CH₃ C₂F₅ CH₂—C≡C-2- furanyl 747 7-CH₃ C₂F₅ CH₂CH═CH-cycPr 748 7-CH₃ C₂F₅ CH₂CH═CH-2- furanyl 749 7-CH₃ C₂F₅ CH═CHCH₂-cycPr 750 7-CH₃ C₂F₅ CH═CHCH₂-2- furanyl 751 7-OCH₃ C₂F₅ n-butyl 752 7-OCH₃ C₂F₅ C≡C—Et 753 7-OCH₃ C₂F₅ C≡C-iPr 754 7-OCH₃ C₂F₅ C≡C-cycPr 755 7-OCH₃ C₂F₅ C≡C-2-pyridyl 756 7-OCH₃ C₂F₅ C≡C-3-pyridyl 757 7-OCH₃ C₂F₅ C≡C-2-furanyl 758 7-OCH₃ C₂F₅ C≡C-3-furanyl 759 7-OCH₃ C₂F₅ C≡C-2-thienyl 760 7-OCH₃ C₂F₅ C≡C-3-thienyl 761 7-OCH₃ C₂F₅ CH═CH—Et 762 7-OCH₃ C₂F₅ CH═CH-iPr 763 7-OCH₃ C₂F₅ CH═CH-cycPr 764 7-OCH₃ C₂F₅ CH═CH-2-pyridyl 765 7-OCH₃ C₂F₅ CH═CH-3-pyridyl 766 7-OCH₃ C₂F₅ CH═CH-2-furanyl 767 7-OCH₃ C₂F₅ CH═CH-3-furanyl 768 7-OCH₃ C₂F₅ CH═CH-2-thienyl 769 7-OCH₃ C₂F₅ CH═CH-3-thienyl 770 7-OCH₃ C₂F₅ CH₂—C≡C-cycPr 771 7-OCH₃ C₂F₅ CH₂—C≡C-2- furanyl 772 7-OCH₃ C₂F₅ CH₂CH═CH-cycPr 773 7-OCH₃ C₂F₅ CH₂CH═CH-2- furanyl 774 7-OCH₃ C₂F₅ CH═CHCH₂-cycPr 775 7-OCH₃ C₂F₅ CH═CHCH₂-2- furanyl 776 7-pyrazol- C₂F₅ n-butyl 6-yl 777 7-pyrazol- C₂F₅ C≡C—Et 6-yl 778 7-pyrazol- C₂F₅ C≡C-iPr 6-yl 779 7-pyrazol- C₂F₅ C≡C-cycPr 6-yl 780 7-pyrazol- C₂F₅ C≡C-2-pyridyl 6-yl 781 7-pyrazol- C₂F₅ C≡C-3-pyridyl 6-yl 782 7-pyrazol- C₂F₅ C≡C-2-furanyl 6-yl 783 7-pyrazol- C₂F₅ C≡C-3-furanyl 6-yl 784 7-pyrazol- C₂F₅ C≡C-2-thienyl 6-yl 785 7-pyrazol- C₂F₅ C≡C-3-thienyl 6-yl 786 7-pyrazol- C₂F₅ CH═CH—Et 6-yl 787 7-pyrazol- C₂F₅ CH═CH-iPr 6-yl 788 7-pyrazol- C₂F₅ CH═CH-cycPr 6-yl 789 7-pyrazol- C₂F₅ CH═CH-2-pyridyl 6-yl 790 7-pyrazol- C₂F₅ CH═CH-3-pyridyl 6-yl 791 7-pyrazol- C₂F₅ CH═CH-2-furanyl 6-yl 792 7-pyrazol- C₂F₅ CH═CH-3-furanyl 6-yl 793 7-pyrazol- C₂F₅ CH═CH-2-thienyl 6-yl 794 7-pyrazol- C₂F₅ CH═CH-3-thienyl 6-yl 795 7-pyrazol- C₂F₅ CH₂—C≡C-cycPr 6-yl 796 7-pyrazol- C₂F₅ CH₂—C≡C-2- 6-yl furanyl 797 7-pyrazol- C₂F₅ CH₂CH═CH-cycPr 6-yl 798 7-pyrazol- C₂F₅ CH₂CH═CH-2- 6-yl furanyl 799 7-pyrazol- C₂F₅ CH═CHCH₂-cycPr 6-yl 800 7-pyrazol- C₂F₅ CH═CHCH₂-2- 6-yl furanyl 801 6,7-OCH₂O— C₂F₅ n-butyl 802 6,7-OCH₂O— C₂F₅ C≡C—Et 803 6,7-OCH₂O— C₂F₅ C≡C-iPr 804 6,7-OCH₂O— C₂F₅ C≡C-cycPr 805 6,7-OCH₂O— C₂F₅ C≡C-2-pyridyl 806 6,7-OCH₂O— C₂F₅ C≡C-3-pyridyl 807 6,7-OCH₂O— C₂F₅ C≡C-2-furanyl 808 6,7-OCH₂O— C₂F₅ C≡C-3-furanyl 809 6,7-OCH₂O— C₂F₅ C≡C-2-thienyl 810 6,7-OCH₂O— C₂F₅ C≡C-3-thienyl 811 6,7-OCH₂O— C₂F₅ CH═CH—Et 812 6,7-OCH₂O— C₂F₅ CH═CH-iPr 813 6,7-OCH₂O— C₂F₅ CH═CH-cycPr 814 6,7-OCH₂O— C₂F₅ CH═CH-2-pyridyl 815 6,7-OCH₂O— C₂F₅ CH═CH-3-pyridyl 816 6,7-OCH₂O— C₂F₅ CH═CH-2-furanyl 817 6,7-OCH₂O— C₂F₅ CH═CH-3-furanyl 818 6,7-OCH₂O— C₂F₅ CH═CH-2-thienyl 819 6,7-OCH₂O— C₂F₅ CH═CH-3-thienyl 820 6,7-OCH₂O— C₂F₅ CH₂—C≡C-cycPr 821 6,7-OCH₂O— C₂F₅ CH₂—C≡C-2- furanyl 822 6,7-OCH₂O— C₂F₅ CH₂CH═CH-cycPr 823 6,7-OCH₂O— C₂F₅ CH₂CH═CH-2- furanyl 824 6,7-OCH₂O— C₂F₅ CH═CHCH₂-cycPr 825 6,7-OCH₂O— C₂F₅ CH═CHCH₂-2- furanyl 826 7-CONH₂ C₂F₅ n-butyl 827 7-CONH₂ C₂F₅ C≡C—Et 828 7-CONH₂ C₂F₅ C≡C-iPr 829 7-CONH₂ C₂F₅ C≡C-cycPr 830 7-CONH₂ C₂F₅ C≡C-2-pyridyl 831 7-CONH₂ C₂F₅ C≡C-3-pyridyl 832 7-CONH₂ C₂F₅ C≡C-2-furanyl 833 7-CONH₂ C₂F₅ C≡C-3-furanyl 834 7-CONH₂ C₂F₅ C≡C-2-thienyl 835 7-CONH₂ C₂F₅ C≡C-3-thienyl 836 7-CONH₂ C₂F₅ CH═CH—Et 837 7-CONH₂ C₂F₅ CH═CH-iPr 838 7-CONH₂ C₂F₅ CH═CH-cycPr 839 7-CONH₂ C₂F₅ CH═CH-2-pyridyl 840 7-CONH₂ C₂F₅ CH═CH-3-pyridyl 841 7-CONH₂ C₂F₅ CH═CH-2-furanyl 842 7-CONH₂ C₂F₅ CH═CH-3-furanyl 843 7-CONH₂ C₂F₅ CH═CH-2-thienyl 844 7-CONH₂ C₂F₅ CH═CH-3-thienyl 845 7-CONH₂ C₂F₅ CH₂—C≡C-cycPr 846 7-CONH₂ C₂F₅ CH₂—C≡C-2- furanyl 847 7-CONH₂ C₂F₅ CH₂CH═CH-cycPr 848 7-CONH₂ C₂F₅ CH₂CH═CH-2- furanyl 849 7-CONH₂ C₂F₅ CH═CHCH₂-cycPr 850 7-CONH₂ C₂F₅ CH═CHCH₂-2- furanyl 851 6-Cl cycPr n-butyl 852 6-Cl cycPr C≡C—Et 853 6-Cl cycPr C≡C-iPr 854 6-Cl cycPr C≡C-cycPr 855 6-Cl cycPr C≡C-2-pyridyl 856 6-Cl cycPr C≡C-3-pyridyl 857 6-Cl cycPr C≡C-2-furanyl 858 6-Cl cycPr C≡C-3-furanyl 859 6-Cl cycPr C≡C-2-thienyl 860 6-Cl cycPr C≡C-3-thienyl 861 6-Cl cycPr CH═CH—Et 862 6-Cl cycPr CH═CH-iPr 863 6-Cl cycPr CH═CH-cycPr 864 6-Cl cycPr CH═CH-2-pyridyl 865 6-Cl cycPr CH═CH-3-pyridyl 866 6-Cl cycPr CH═CH-2-furanyl 867 6-Cl cycPr CH═CH-3-furanyl 868 6-Cl cycPr CH═CH-2-thienyl 869 6-Cl cycPr CH═CH-3-thienyl 870 6-Cl cycPr CH═C≡C-cycPr 871 6-Cl cycPr CH₂—C≡C-2- furanyl 872 6-Cl cycPr CH₂CH═CH-cycPr 873 6-Cl cycPr CH₂CH═CH-2- furanyl 874 6-Cl cycPr CH═CHCH₂-cycPr 875 6-Cl cycPr CH═CHCH₂-2- furanyl 876 7-Cl cycPr n-butyl 877 7-Cl cycPr C≡C—Et 878 7-Cl cycPr C≡C-iPr 879 7-Cl cycPr C≡C-cycPr 880 7-Cl cycPr C≡C-2-pyridyl 881 7-Cl cycPr C≡C-3-pyridyl 882 7-Cl cycPr C≡C-2-furanyl 883 7-Cl cycPr C≡C-3-furanyl 884 7-Cl cycPr C≡C-2-thienyl 885 7-Cl cycPr C≡C-3-thienyl 886 7-Cl cycPr CH═CH—Et 887 7-Cl cycPr CH═CH-iPr 888 7-Cl cycPr CH═CH-cycPr 889 7-Cl cycPr CH═CH-2-pyridyl 890 7-Cl cycPr CH═CH-3-pyridyl 891 7-Cl cycPr CH═CH-2-furanyl 892 7-Cl cycPr CH═CH-3-furanyl 893 7-Cl cycPr CH═CH-2-thienyl 894 7-Cl cycPr CH═CH-3-thienyl 895 7-Cl cycPr CH₂—C≡C-cycPr 896 7-Cl cycPr CH₂C≡C-2- furanyl 897 7-Cl cycPr CH₂CH═CH-cycPr 898 7-Cl cycPr CH₂CH═CH-2- furanyl 899 7-Cl cycPr CH═CHCH₂-cycPr 900 7-Cl cycPr CH═CHCH₂-2- furanyl 901 6-F cycPr n-butyl 902 6-F cycPr C≡C—Et 903 6-F cycPr C≡C-iPr 904 6-F cycPr C≡C-cycPr 905 6-F cycPr C≡C-2-pyridyl 906 6-F cycPr C≡C-3-pyridyl 907 6-F cycPr C≡C-2-furanyl 908 6-F cycPr C≡C-3-furanyl 909 6-F cycPr C≡C-2-thienyl 910 6-F cycPr C≡C-3-thienyl 911 6-F cycPr CH═CH—Et 912 6-F cycPr CH═CH-iPr 913 6-F cycPr CH═CH-cycPr 914 6-F cycPr CH═CH-2-pyridyl 915 6-F cycPr CH═CH-3-pyridyl 916 6-F cycPr CH═CH-2-furanyl 917 6-F cycPr CH═CH-3-furanyl 918 6-F cycPr CH═CH-2-thienyl 919 6-F cycPr CH═CH-3-thienyl 920 6-F cycPr CH₂—C≡C-cycPr 921 6-F cycPr CH₂—C≡C-2- furanyl 922 6-F cycPr CH₂CH═CH-cycPr 923 6-F cycPr CH₂CH═CH-2- furanyl 924 6-F cycPr CH═CHCH₂-cycPr 925 6-F cycPr CH═CHCH₂-2- furanyl 926 7-F cycPr n-butyl 927 7-F cycPr C≡C—Et 928 7-F cycPr C≡C-iPr 929 7-F cycPr C≡C-cycPr 930 7-F cycPr C≡C-2-pyridyl 931 7-F cycPr C≡C-3-pyridyl 932 7-F cycPr C≡C-2-furanyl 933 7-F cycPr C≡C-3-furanyl 934 7-F cycPr C≡C-2-thienyl 935 7-F cycPr C≡C-3-thienyl 936 7-F cycPr CH═CH—Et 937 7-F cycPr CH═CH-iPr 938 7-F cycPr CH═CH-cycPr 939 7-F cycPr CH═CH-2-pyridyl 940 7-F cycPr CH═CH-3-pyridyl 941 7-F cycPr CH═CH-2-furanyl 942 7-F cycPr CH═CH-3-furanyl 943 7-F cycPr CH═CH-2-thienyl 944 7-F cycPr CH═CH-3-thienyl 945 7-F cycPr CH₂—C≡C-cycPr 946 7-F cycPr CH₂—C≡C-2- furanyl 947 7-F cycPr CH₂CH═CH-cycPr 948 7-F cycPr CH₂CH═CH-2- furanyl 949 7-F cycPr CH═CHCH₂-cycPr 950 7-F cycPr CH═CHCH₂-2- furanyl 951 6,7-diCl cycPr n-butyl 952 6,7-diCl cycPr C≡C—Et 953 6,7-diCl cycPr C≡C-iPr 954 6,7-diCl cycPr C≡C-cycPr 955 6,7-diCl cycPr C≡C-2-pyridyl 956 6,7-diCl cycPr C≡C-3-pyridyl 957 6,7-diCl cycPr C≡C-2-furanyl 958 6,7-diCl cycPr C≡C-3-furanyl 959 6,7-diCl cycPr C≡C-2-thienyl 960 6,7-diCl cycPr C≡C-3-thienyl 961 6,7-diCl cycPr CH═CH—Et 962 6,7-diCl cycPr CH═CH-iPr 963 6,7-diCl cycPr CH═CH-cycPr 964 6,7-diCl cycPr CH═CH-2-pyridyl 965 6,7-diCl cycPr CH═CH-3-pyridyl 966 6,7-diCl cycPr CH═CH-2-furanyl 967 6,7-diCl cycPr CH═CH-3-furanyl 968 6,7-diCl cycPr CH═CH-2-thienyl 969 6,7-diCl cycPr CH═CH-3-thienyl 970 6,7-diCl cycPr CH₂—C≡C-cycPr 971 6,7-diCl cycPr CH₂—C≡C-2- furanyl 972 6,7-diCl cycPr CH₂CH═CH-cycPr 973 6,7-diCl cycPr CH₂CH═CH-2- furanyl 974 6,7-diCl cycPr CH═CHCH₂-cycPr 975 6,7-diCl cycPr CH═CHCH₂-2- furanyl 976 6,7-diF cycPr n-butyl 977 6,7-diF cycPr C≡C—Et 978 6,7-diF cycPr C≡C-iPr 979 6,7-diF cycPr C≡C-cycPr 980 6,7-diF cycPr C≡C-2-pyridyl 981 6,7-diF cycPr C≡C-3-pyridyl 982 6,7-diF cycPr C≡C-2-furanyl 983 6,7-diF cycPr C≡C-3-furanyl 984 6,7-diF cycPr C≡C-2-thienyl 985 6,7-diF cycPr C≡C-3-thienyl 986 6,7-diF cycPr CH═CH—Et 987 6,7-diF cycPr CH═CH-iPr 988 6,7-diF cycPr CH═CH-cycPr 989 6,7-diF cycPr CH═CH-2-pyridyl 990 6,7-diF cycPr CH═CH-3-pyridyl 991 6,7-diF cycPr CH═CH-2-furanyl 992 6,7-diF cycPr CH═CH-3-furanyl 993 6,7-diF cycPr CH═CH-2-thienyl 994 6,7-diF cycPr CH═CH-3-thienyl 995 6,7-diF cycPr CH₂—C≡C-cycPr 996 6,7-diF cycPr CH₂—C≡C-2- furanyl 997 6,7-diF cycPr CH₂CH═CH-cycPr 998 6,7-diF cycPr CH₂CH═CH-2- furanyl 999 6,7-diF cycPr CH═CHCH₂-cycPr 1000 6,7-diF cycPr CH═CHCH₂-2- furanyl 1001 6-Cl, 7-F cycPr n-butyl 1002 6-Cl, 7-F cycPr C≡C—Et 1003 6-Cl, 7-F cycPr C≡C-iPr 1004 6-Cl, 7-F cycPr C≡C-cycPr 1005 6-Cl, 7-F cycPr C≡C-2-pyridyl 1006 6-Cl, 7-F cycPr C≡C-3-pyridyl 1007 6-Cl, 7-F cycPr C≡C-2-furanyl 1008 6-Cl, 7-F cycPr C≡C-3-furanyl 1009 6-Cl, 7-F cycPr C≡C-2-thienyl 1010 6-Cl, 7-F cycPr C≡C-3-thienyl 1011 6-Cl, 7-F cycPr CH═CH—Et 1012 6-Cl, 7-F cycPr CH═CH-iPr 1013 6-Cl, 7-F cycPr CH═CH-cycPr 1014 6-Cl, 7-F cycPr CH═CH-2-pyridyl 1015 6-Cl, 7-F cycPr CH═CH-3-pyridyl 1016 6-Cl, 7-F cycPr CH═CH-2-furanyl 1017 6-Cl, 7-F cycPr CH═CH-3-furanyl 1018 6-Cl, 7-F cycPr CH═CH-2-thienyl 1019 6-Cl, 7-F cycPr CH═CH-3-thienyl 1020 6-Cl, 7-F cycPr CH₂—C≡C-cycPr 1021 6-Cl, 7-F cycPr CH₂—C≡C-2- furanyl 1022 6-Cl, 7-F cycPr CH₂CH═CH-cycPr 1023 6-Cl, 7-F cycPr CH₂CH═CH-2- furanyl 1024 6-Cl, 7-F cycPr CH═CHCH₂-cycPr 1025 6-Cl, 7-F cycPr CH═CHCH₂-2- furanyl 1026 6-F, 7-Cl cycPr n-butyl 1027 6-F, 7-Cl cycPr C≡C—Et 1028 6-F, 7-Cl cycPr C≡C-iPr 1029 6-F, 7-Cl cycPr C≡C-cycPr 1030 6-F, 7-Cl cycPr C≡C-2-pyridyl 1031 6-F, 7-Cl cycPr C≡C-3-pyridyl 1032 6-F, 7-Cl cycPr C≡C-2-furanyl 1033 6-F, 7-Cl cycPr C≡C-3-furanyl 1034 6-F, 7-Cl cycPr C≡C-2-thienyl 1035 6-F, 7-Cl cycPr C≡C-3-thieny1 1036 6-F, 7-Cl cycPr CH═CH—Et 1037 6-F, 7-Cl cycPr CH═CH-iPr 1038 6-F, 7-Cl cycPr CH═CH-cycPr 1039 6-F, 7-Cl cycPr CH═CH-2-pyridyl 1040 6-F, 7-Cl cycPr CH═CH-3-pyridyl 1041 6-F, 7-Cl cycPr CH═CH-2-furanyl 1042 6-F, 7-Cl cycPr CH═CH-3-furanyl 1043 6-F, 7-Cl cycPr CH═CH-2-thienyl 1044 6-F, 7-Cl cycPr CH═CH-3-thienyl 1045 6-F, 7-Cl cycPr CH₂—C≡C-cycPr 1046 6-F, 7-Cl cycPr CH₂—C≡C-2- furanyl 1047 6-F, 7-Cl cycPr CH₂CH═CH-cycPr 1048 6-F, 7-Cl cycPr CH₂CH═CH-2- furanyl 1049 6-F, 7-Cl cycPr CH═CHCH₂-cycPr 1050 6-F, 7-Cl cycPr CH═CHCH₂-2- furanyl 1051 7-CH₃ cycPr n-butyl 1052 7-CH₃ cycPr C≡C—Et 1053 7-CH₃ cycPr C≡C-iPr 1054 7-CH₃ cycPr C≡C-cycPr 1055 7-CH₃ cycPr C≡C-2-pyridyl 1056 7-CH₃ cycPr C≡C-3-pyridyl 1057 7-CH₃ cycPr C≡C-2-furanyl 1058 7-CH₃ cycPr C≡C-3-furanyl 1059 7-CH₃ cycPr C≡C-2-thienyl 1060 7-CH₃ cycPr C≡C-3-thienyl 1061 7-CH₃ cycPr CH═CH—Et 1062 7-CH₃ cycPr CH═CH-iPr 1063 7-CH₃ cycPr CH═CH-cycPr 1064 7-CH₃ cycPr CH═CH-2-pyridyl 1065 7-CH₃ cycPr CH═CH-3-pyridyl 1066 7-CH₃ cycPr CH═CH-2-furanyl 1067 7-CH₃ cycPr CH═CH-3-furanyl 1068 7-CH₃ cycPr CH═CH-2-thienyl 1069 7-CH₃ cycPr CH═CH-3-thienyl 1070 7-CH₃ cycPr CH₂—C≡C-cycPr 1071 7-CH₃ cycPr CH₂—C≡C-2- furanyl 1072 7-CH₃ cycPr CH₂CH═CH-cycPr 1073 7-CH₃ cycPr CH₂CH═CH-2- furanyl 1074 7-CH₃ cycPr CH═CHCH₂-cycPr 1075 7-CH₃ cycPr CH═CHCH₂-2- furanyl 1076 7-OCH₃ cycPr n-butyl 1077 7-OCH₃ cycPr C≡C—Et 1078 7-OCH₃ cycPr C≡C-iPr 1079 7-OCH₃ cycPr C≡C-cycPr 1080 7-OCH₃ cycPr C≡C-2-pyridyl 1081 7-OCH₃ cycPr C≡C-3-pyridyl 1082 7-OCH₃ cycPr C≡C-2-furanyl 1083 7-OCH₃ cycPr C≡C-3-furanyl 1084 7-OCH₃ cycPr C≡C-2-thienyl 1085 7-OCH₃ cycPr C≡C-3-thienyl 1086 7-OCH₃ cycPr CH═CH—Et 1087 7-OCH₃ cycPr CH═CH-iPr 1088 7-OCH₃ cycPr CH═CH-cycPr 1089 7-OCH₃ cycPr CH═CH-2-pyridyl 1090 7-OCH₃ cycPr CH═CH-3-pyridyl 1091 7-OCH₃ cycPr CH═CH-2-furanyl 1092 7-OCH₃ cycPr CH═CH-3-furanyl 1093 7-OCH₃ cycPr CH═CH-2-thienyl 1094 7-OCH₃ cycPr CH═CH-3-thienyl 1095 7-OCH₃ cycPr CH₂—C≡C-cycPr 1096 7-OCH₃ cycPr CH₂—C≡C-2- furanyl 1097 7-OCH₃ cycPr CH₂CH═CH-cycPr 1098 7-OCH₃ cycPr CH₂CH═CH-2- furanyl 1099 7-OCH₃ cycPr CH═CHCH₂-cycPr 1100 7-OCH₃ cycPr CH═CHCH₂-2- furanyl 1101 7-pyrazol- cycPr n-butyl 6-yl 1102 7-pyrazol- cycPr C≡C—Et 6-yl 1103 7-pyrazol- cycPr C≡C-iPr 6-yl 1104 7-pyrazol- cycPr C≡C-cycPr 6-yl 1105 7-pyrazol- cycPr C≡C-2-pyridyl 6-yl 1106 7-pyrazol- cycPr C≡C-3-pyridyl 6-yl 1107 7-pyrazol- cycPr C≡C-2-furanyl 6-yl 1108 7-pyrazol- cycPr C≡C-3-furanyl 6-yl 1109 7-pyrazol- cycPr C≡C-2-thienyl 6-yl 1110 7-pyrazol- cycPr C≡C-3-thienyl 6-yl 1111 7-pyrazol- cycPr CH═CH—Et 6-yl 1112 7-pyrazol- cycPr CH═CH-iPr 6-yl 1113 7-pyrazol- cycPr CH═CH-cycPr 6-yl 1114 7-pyrazol- cycPr CH═CH-2-pyridyl 6-yl 1115 7-pyrazol- cycPr CH═CH-3-pyridyl 6-yl 1116 7-pyrazol- cycPr CH═CH-2-furanyl 6-yl 1117 7-pyrazol- cycPr CH═CH-3-furanyl 6-yl 1118 7-pyrazol- cycPr CH═CH-2-thienyl 6-yl 1119 7-pyrazol- cycPr CH═CH-3-thienyl 6-yl 1120 7-pyrazol- cycPr CH₂—C≡C-cycPr 6-yl 1121 7-pyrazol- cycPr CH₂—C≡C-2- 6-yl furanyl 1122 7-pyrazol- cycPr CH₂CH═CH-cycPr 6-yl 1123 7-pyrazol- cycPr CH₂—CH═CH-2- 6-yl furanyl 1124 7-pyrazol- cycPr CH═CHCH₂-cycPr 6-yl 1125 7-pyrazol- cycPr CH═CHCH₂-2- 6-yl furanyl 1126 6,7-OCH₂O— cycPr n-butyl 1127 6,7-OCH₂O— cycPr C≡C—Et 1128 6,7-OCH₂O— cycPr C≡C-iPr 1129 6,7-OCH₂O— cycPr C≡C-cycPr 1130 6,7-OCH₂O— cycPr C≡C-2-pyridyl 1131 6,7-OCH₂O— cycPr C≡C-3-pyridyl 1132 6,7-OCH₂O— cycPr C≡C-2-furanyl 1133 6,7-OCH₂O— cycPr C≡C-3-furanyl 1134 6,7-OCH₂O— cycPr C≡C-2-thienyl 1135 6,7-OCH₂O— cycPr C≡C-3-thienyl 1136 6,7-OCH₂O— cycPr CH═CH—Et 1137 6,7-OCH₂O— cycPr CH═CH-iPr 1138 6,7-OCH₂O— cycPr CH═CH-cycPr 1139 6,7-OCH₂O— cycPr CH═CH-2-pyridyl 1140 6,7-OCH₂O— cycPr CH═CH-3-pyridyl 1141 6,7-OCH₂O— cycPr CH═CH-2-furanyl 1142 6,7-OCH₂O— cycPr CH═CH-3-furanyl 1143 6,7-OCH₂O— cycPr CH═CH-2-thienyl 1144 6,7-OCH₂O— cycPr CH═CH-3-thienyl 1145 6,7-OCH₂O— cycPr CH₂—C≡C-cycPr 1146 6,7-OCH₂O— cycPr CH₂—C≡C-2- furanyl 1147 6,7-OCH₂O— cycPr CH₂CH═CH-cycPr 1148 6,7-OCH₂O— cycPr CH₂CH═CH-2- furanyl 1149 6,7-OCH₂O— cycPr CH═CHCH₂-cycPr 1150 6,7-OCH₂O— cycPr CH═CHCH₂-2- furanyl 1151 6,7-OCH₂O— cycPr n-butyl 1152 7-CONH₂ cycPr C≡C—Et 1153 7-CONH₂ cycPr C≡C-iPr 1154 7-CONH₂ cycPr C≡C-cycPr 1155 7-CONH₂ cycPr C≡C-2-pyridyl 1156 7-CONH₂ cycPr C≡C-3-pyridyl 1157 7-CONH₂ cycPr C≡C-2-furanyl 1158 7-CONH₂ cycPr C≡C-3-furanyl 1159 7-CONH₂ cycPr C≡C-2-thienyl 1160 7-CONH₂ cycPr C≡C-3-thienyl 1161 7-CONH₂ cycPr CH═CH—Et 1162 7-CONH₂ cycPr CH═CH-iPr 1163 7-CONH₂ cycPr CH═CH-cycPr 1164 7-CONH₂ cycPr CH═CH-2-pyridyl 1165 7-CONH₂ cycPr CH═CH-3-pyridyl 1166 7-CONH₂ cycPr CH═CH-2-furanyl 1167 7-CONH₂ cycPr CH═CH-3-furanyl 1168 7-CONH₂ cycPr CH═CH-2-thienyl 1169 7-CONH₂ cycPr CH═CH-3-thienyl 1170 7-CONH₂ cycPr CH₂—C≡C-cycPr 1171 7-CONH₂ cycPr CH₂—C≡C-2- furanyl 1172 7-CONH₂ cycPr CH₂CH═CH-cycPr 1173 7-CONH₂ cycPr CH₂CH═CH-2- furanyl 1174 7-CONH₂ cycPr CH═CHCH₂-cycPr 1175 7-CONH₂ cycPr CH═CHCH₂-2- furanyl *Unless otherwise noted, stereochemistry is (+/−) and in R², all double bonds are trans.

TABLE 3

Ex. # W X Y Z R¹ R² 2001 CH CCl CH N CF₃ C≡C-nPr 2002 CH CCl CH N CF₃ C≡C-Bu 2003 CH CCl CH N CF₃ C≡C-iBu 2004 CH CCl CH N CF₃ C≡C-tBu 2005 CH CCl CH N CF₃ C≡C-Et 2006 CH CCl CH N CF₃ C≡C-Me 2007 CH CCl CH N CF₃ C≡C-Ph 2008 CH CCl CH N CF₃ C≡C-2-Pyridyl 2009 CH CCl CH N CF₃ C≡C-3-Pyridyl 2010 CH CCl CH N CF₃ C≡C-4-Pyridyl 2011 CH CCl CH N CF₃ C≡C-2-furanyl 2012 CH CCl CH N CF₃ C≡C-3-furanyl 2013 CH CCl CH N CF₃ C≡C-2-thienyl 2014 CH CCl CH N CF₃ C≡C-3-thienyl 2015 CH CCl CH N CF₃ CH═CH-cycPr 2016 CH CCl CH N CF₃ CH═CH-iPr 2017 CH CCl CH N CF₃ CH═CH-nPr 2018 CH CCl CH N CF₃ CH═CH-Bu 2019 CH CCl CH N CF₃ CH═CH-iBu 2020 CH CCl CH N CF₃ CH═CH-tBu 2021 CH CCl CH N CF₃ CH═CH-Et 2022 CH CCl CH N CF₃ CH═CH-Me 2023 CH CCl CH N CF₃ CH═CH-Ph 2024 CH CCl CH N CF₃ CH═CH-2-Pyridyl 2025 CH CCl CH N CF₃ CH═CH-3-Pyridyl 2026 CH CCl CH N CF₃ CH═CH-4-Pyridyl 2027 CH CCl CH N CF₃ CH═CH-2-furanyl 2028 CH CCl CH N CF₃ CH═CH-3-furanyl 2029 CH CCl CH N CF₃ CH═CH-2-thienyl 2030 CH CCl CH N CF₃ CH═CH-3-thienyl 2031 CH CCl CH N CF₃ CH₂CH₂CH₂CH₂CH₃ 2032 CH CCl CH N CF₃ CH₂CH₂CH(CH₃)₂ 2033 CH CCl CH N CF₃ CH₂CH₂CH₂CH₃ 2034 CH CCl CH N CF₃ CH₂CH₂CH₃ 2035 CH CCl CH N CF₃ CH₂CH₂-cycPr 2036 CH CCl CH N CF₃ CH₂CH₂-tBu 2037 CH CCl CH N CF₃ CH₂CH₂-2-Pyridyl 2038 CH CCl CH N CF₃ CH₂CH₂-3-Pyridyl 2039 CH CCl CH N CF₃ CH₂CH₂-4-Pyridyl 2040 CH CCl CH N CF₃ CH₂CH₂-2-furanyl 2041 CH CCl CH N CF₃ CH₂CH₂-3-furanyl 2042 CH CCl CH N CF₃ CH₂CH₂-2-thienyl 2043 CH CCl CH N CF₃ CH₂CH₂-3-thienyl 2044 CH C(OCH₃) CH N CF₃ C≡C-cycPr 2045 CH C(OCH₃) CH N CF₃ C≡C-iPr 2046 CH C(OCH₃) CH N CF₃ C≡C-nPr 2047 CH C(OCH₃) CH N CF₃ C≡C-Bu 2048 CH C(OCH₃) CH N CF₃ C≡C-iBu 2049 CH C(OCH₃) CH N CF₃ C≡C-tBu 2050 CH C(OCH₃) CH N CF₃ C≡C-Et 2051 CH C(OCH₃) CH N CF₃ C≡C-Me 2052 CH C(OCH₃) CH N CF₃ C≡C-Ph 2053 CH C(OCH₃) CH N CF₃ C≡C-2-Pyridyl 2054 CH C(OCH₃) CH N CF₃ C≡C-3-Pyridyl 2055 CH C(OCH₃) CH N CF₃ C≡C-4-Pyridyl 2056 CH C(OCH₃) CH N CF₃ C≡C-2-furanyl 2057 CH C(OCH₃) CH N CF₃ C≡C-3-furanyl 2058 CH C(OCH₃) CH N CF₃ C≡C-2-thienyl 2059 CH C(OCH₃) CH N CF₃ C≡C-3-thienyl 2060 CH C(OCH₃) CH N CF₃ CH═CH-cycPr 2061 CH C(OCH₃) CH N CF₃ CH═CH-iPr 2062 CH C(OCH₃) CH N CF₃ CH═CH-nPr 2063 CH C(OCH₃) CH N CF₃ CH═CH-Bu 2064 CH C(OCH₃) CH N CF₃ CH═CH-iBu 2065 CH C(OCH₃) CH N CF₃ CH═CH-tBu 2066 CH C(OCH₃) CH N CF₃ CH═CH-Et 2067 CH C(OCH₃) CH N CF₃ CH═CH-Me 2068 CH C(OCH₃) CH N CF₃ CH═CH-Ph 2069 CH C(OCH₃) CH N CF₃ CH═CH-2-Pyridyl 2070 CH C(OCH₃) CH N CF₃ CH═CH-3-Pyridyl 2071 CH C(OCH₃) CH N CF₃ CH═CH-4-Pyridyl 2072 CH C(OCH₃) CH N CF₃ CH═CH-2-furanyl 2073 CH C(OCH₃) CH N CF₃ CH═CH-3-furanyl 2074 CH C(OCH₃) CH N CF₃ CH═CH-2-thienyl 2075 CH C(OCH₃) CH N CF₃ CH═CH-3-thienyl 2076 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₂CH₂CH₃ 2077 CH C(OCH₃) CH N CF₃ CH₂CH₂CH(CH₃)₂ 2078 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₂CH₃ 2079 CH C(OCH₃) CH N CF₃ CH₂CH₂CH₃ 2080 CH C(OCH₃) CH N CF₃ CH₂CH₂-cycPr 2081 CH C(OCH₃) CH N CF₃ CH₂CH₂-tBu 2082 CH C(OCH₃) CH N CF₃ CH₂CH₂-Ph 2083 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-Pyridyl 2084 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-Pyridyl 2085 CH C(OCH₃) CH N CF₃ CH₂CH₂-4-Pyridyl 2086 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-furanyl 2087 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-furanyl 2088 CH C(OCH₃) CH N CF₃ CH₂CH₂-2-thienyl 2089 CH C(OCH₃) CH N CF₃ CH₂CH₂-3-thienyl 2090 CH CH CH N CF₃ C≡C-cycPr 2091 CH CH CH N CF₃ C≡C-iPr 2092 CH CH CH N CF₃ C≡C-nPr 2093 CH CH CH N CF₃ C≡C-Et 2094 CH CH CH N CF₃ C≡C-3-Pyridyl 2095 CH CH CH N CF₃ C≡C-2-furanyl 2096 CH CH CH N CF₃ C≡C-3-furanyl 2097 CH CH CH N CF₃ C≡C-2-thienyl 2098 CH CH CH N CF₃ C≡C-3-thienyl 2099 CH CCl N CH CF₃ C≡C-iPr 2100 CH CCl N CH CF₃ C≡C-nPr 2101 CH CCl N CH CF₃ C≡C-Bu 2102 CH CCl N CH CF₃ C≡C-iBu 2103 CH CCl N CH CF₃ C≡C-tBu 2104 CH CCl N CH CF₃ C≡C-Et 2105 CH CCl N CH CF₃ C≡C-Me 2106 CH CCl N CH CF₃ C≡C-Ph 2107 CH CCl N CH CF₃ C≡C-2-Pyridyl 2108 CH CCl N CH CF₃ C≡C-3-Pyridyl 2109 CH CCl N CH CF₃ C≡C-4-Pyridyl 2110 CH CCl N CH CF₃ C≡C-2-furanyl 2111 CH CCl N CH CF₃ C≡C-3-furanyl 2112 CH CCl N CH CF₃ C≡C-2-thienyl 2113 CH CCl N CH CF₃ C≡C-3-thienyl 2114 CH CCl N CH CF₃ CH═CH-cycPr 2115 CH CCl N CH CF₃ CH═CH-iPr 2116 CH CCl N CH CF₃ CH═CH-nPr 2117 CH CCl N CH CF₃ CH═CH-Bu 2118 CH CCl N CH CF₃ CH═CH-iBu 2119 CH CCl N CH CF₃ CH═CH-tBu 2120 CH CCl N CH CF₃ CH═CH-Et 2121 CH CCl N CH CF₃ CH═CH-Me 2122 CH CCl N CH CF₃ CH═CH-Ph 2123 CH CCl N CH CF₃ CH═CH-2-Pyridyl 2124 CH CCl N CH CF₃ CH═CH-3-Pyridyl 2125 CH CCl N CH CF₃ CH═CH-4-Pyridyl 2126 CH CCl N CH CF₃ CH═CH-2-furanyl 2127 CH CCl N CH CF₃ CH═CH-3-furanyl 2128 CH CCl N CH CF₃ CH═CH-2-thienyl 2129 CH CCl N CH CF₃ CH═CH-3-thienyl 2130 CH CCl N CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2131 CH CCl N CH CF₃ CH₂CH₂CH(CH₃)₂ 2132 CH CCl N CH CF₃ CH₂CH₂CH₂CH₃ 2133 CH CCl N CH CF₃ CH₂CH₂CH₃ 2134 CH CCl N CH CF₃ CH₂CH₂-cycPr 2135 CH CCl N CH CF₃ CH₂CH₂-tBu 2136 CH CCl N CH CF₃ CH₂CH₂-Ph 2137 CH CCl N CH CF₃ CH₂CH₂-2-Pyridyl 2138 CH CCl N CH CF₃ CH₂CH₂-3-Pyridyl 2139 CH CCl N CH CF₃ CH₂CH₂-4-Pyridyl 2140 CH CCl N CH CF₃ CH₂CH₂-2-furanyl 2141 CH CCl N CH CF₃ CH₂CH₂-3-furanyl 2142 CH CCl N CH CF₃ CH₂CH₂-2-thienyl 2143 CH CCl N CH CF₃ CH₂CH₂-3-thienyl 2144 CH C(OCH₃) N CH CF₃ C≡C-iPr 2145 CH C(OCH₃) N CH CF₃ C≡C-nPr 2146 CH C(OCH₃) N CH CF₃ C≡C-Bu 2147 CH C(OCH₃) N CH CF₃ C≡C-iBu 2148 CH C(OCH₃) N CH CF₃ C≡C-tBu 2149 CH C(OCH₃) N CH CF₃ C≡C-Et 2150 CH C(OCH₃) N CH CF₃ C≡C-Me 2151 CH C(OCH₃) N CH CF₃ C≡C-Ph 2152 CH C(OCH₃) N CH CF₃ C≡C-2-Pyridyl 2153 CH C(OCH₃) N CH CF₃ C≡C-3-Pyridyl 2154 CH C(OCH₃) N CH CF₃ C≡C-4-Pyridyl 2155 CH C(OCH₃) N CH CF₃ C≡C-2-furanyl 2156 CH C(OCH₃) N CH CF₃ C≡C-3-furanyl 2157 CH C(OCH₃) N CH CF₃ C≡C-2-thienyl 2158 CH C(OCH₃) N CH CF₃ C≡C-3-thienyl 2159 CH C(OCH₃) N CH CF₃ CH═CH-cycPr 2160 CH C(OCH₃) N CH CF₃ CH═CH-iPr 2161 CH C(OCH₃) N CH CF₃ CH═CH-nPr 2162 CH C(OCH₃) N CH CF₃ CH═CH-Bu 2163 CH C(OCH₃) N CH CF₃ CH═CH-iBu 2164 CH C(OCH₃) N CH CF₃ CH═CH-tBu 2165 CH C(OCH₃) N CH CF₃ CH═CH-Et 2166 CH C(OCH₃) N CH CF₃ CH═CH-Me 2167 CH C(OCH₃) N CH CF₃ CH═CH-Ph 2168 CH C(OCH₃) N CH CF₃ CH═CH-2-Pyridyl 2169 CH C(OCH₃) N CH CF₃ CH═CH-3-Pyridyl 2170 CH C(OCH₃) N CH CF₃ CH═CH-4-Pyridyl 2171 CH C(OCH₃) N CH CF₃ CH═CH-2-furanyl 2172 CH C(OCH₃) N CH CF₃ CH═CH-3-furanyl 2173 CH C(OCH₃) N CH CF₃ CH═CH-2-thienyl 2174 CH C(OCH₃) N CH CF₃ CH═CH-3-thienyl 2175 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2176 CH C(OCH₃) N CH CF₃ CH₂CH₂CH(CH₃)₂ 2177 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₂CH₃ 2178 CH C(OCH₃) N CH CF₃ CH₂CH₂CH₃ 2179 CH C(OCH₃) N CH CF₃ CH₂CH₂-cycPr 2180 CH C(OCH₃) N CH CF₃ CH₂CH₂-tBu 2181 CH C(OCH₃) N CH CF₃ CH₂CH₂-Ph 2182 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-Pyridyl 2183 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-Pyridyl 2184 CH C(OCH₃) N CH CF₃ CH₂CH₂-4-Pyridyl 2185 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-furanyl 2186 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-furanyl 2187 CH C(OCH₃) N CH CF₃ CH₂CH₂-2-thienyl 2188 CH C(OCH₃) N CH CF₃ CH₂CH₂-3-thienyl 2189 CH CH N CH CF₃ C≡C-cycPr 2190 CH CH N CH CF₃ C≡C-iPr 2191 CH CH N CH CF₃ C≡C-nPr 2192 CH CH N CH CF₃ C≡C-Et 2193 CH CH N CH CF₃ C≡C-3-Pyridyl 2194 CH CH N CH CF₃ C≡C-2-furanyl 2195 CH CH N CH CF₃ C≡C-3-furanyl 2196 CH CH N CH CF₃ C≡C-2-thienyl 2197 CH CH N CH CF₃ C≡C-3-thienyl 2198 CCl N CH CH CF₃ C≡C-cycPr 2199 CCl N CH CH CF₃ C≡C-iPr 2200 CCl N CH CH CF₃ C≡C-nPr 2201 CCl N CH CH CF₃ C≡C-Bu 2202 CCl N CH CH CF₃ C≡C-iBu 2203 CCl N CH CH CF₃ C≡C-tBu 2204 CCl N CH CH CF₃ C≡C-Et 2205 CCl N CH CH CF₃ C≡C-Me 2206 CCl N CH CH CF₃ C≡C-Ph 2207 CCl N CH CH CF₃ C≡C-2-Pyridyl 2208 CCl N CH CH CF₃ C≡C-3-Pyridyl 2209 CCl N CH CH CF₃ C≡C-4-Pyridyl 2210 CCl N CH CH CF₃ C≡C-2-furanyl 2211 CCl N CH CH CF₃ C≡C-3-furanyl 2212 CCl N CH CH CF₃ C≡C-2-thienyl 2213 CCl N CH CH CF₃ C≡C-3-thienyl 2214 CCl N CH CH CF₃ CH═CH-cycPr 2215 CCl N CH CH CF₃ CH═CH-iPr 2216 CCl N CH CH CF₃ CH═CH-nPr 2217 CCl N CH CH CF₃ CH═CH-Bu 2218 CCl N CH CH CF₃ CH═CH-iBu 2219 CCl N CH CH CF₃ CH═CH-tBu 2220 CCl N CH CH CF₃ CH═CH-Et 2221 CCl N CH CH CF₃ CH═CH-Me 2222 CCl N CH CH CF₃ CH═CH-Ph 2223 CCl N CH CH CF₃ CH═CH-2-Pyridyl 2224 CCl N CH CH CF₃ CH═CH-3-Pyridyl 2225 CCl N CH CH CF₃ CH═CH-4-Pyridyl 2226 CCl N CH CH CF₃ CH═CH-2-furanyl 2227 CCl N CH CH CF₃ CH═CH-3-furanyl 2228 CCl N CH CH CF₃ CH═CH-2-thienyl 2229 CCl N CH CH CF₃ CH═CH-3-thienyl 2230 CCl N CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2231 CCl N CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2232 CCl N CH CH CF₃ CH₂CH₂CH₂CH₃ 2233 CCl N CH CH CF₃ CH₂CH₂CH₃ 2234 CCl N CH CH CF₃ CH₂CH₂-cycPr 2235 CCl N CH CH CF₃ CH₂CH₂-tBu 2236 CCl N CH CH CF₃ CH₂CH₂-Ph 2237 CCl N CH CH CF₃ CH₂CH₂-2-Pyridyl 2238 CCl N CH CH CF₃ CH₂CH₂-3-Pyridyl 2239 CCl N CH CH CF₃ CH₂CH₂-4-Pyridyl 2240 CCl N CH CH CF₃ CH₂CH₂-2-furanyl 2241 CCl N CH CH CF₃ CH₂CH₂-3-furanyl 2242 CCl N CH CH CF₃ CH₂CH₂-2-thienyl 2243 CCl N CH CH CF₃ CH₂CH₂-3-thienyl 2244 CH N CH CH CF₃ C≡C-iPr 2245 CH N CH CH CF₃ C≡C-nPr 2246 CH N CH CH CF₃ C≡C-Et 2247 CH N CH CH CF₃ C≡C-3-Pyridyl 2248 CH N CH CH CF₃ C≡C-2-furanyl 2249 CH N CH CH CF₃ C≡C-3-furanyl 2250 CH N CH CH CF₃ C≡C-2-thienyl 2251 CH N CH CH CF₃ C≡C-3-thienyl 2252 N CCl CH CH CF₃ C≡C-cycPr 2253 N CCl CH CH CF₃ C≡C-iPr 2254 N CCl CH CH CF₃ C≡C-nPr 2255 N CCl CH CH CF₃ C≡C-Bu 2256 N CCl CH CH CF₃ C≡C-iBu 2257 N CCl CH CH CF₃ C≡C-tBu 2258 N CCl CH CH CF₃ C≡C-Et 2259 N CCl CH CH CF₃ C≡C-Me 2260 N CCl CH CH CF₃ C≡C-Ph 2261 N CCl CH CH CF₃ C≡C-2-Pyridyl 2262 N CCl CH CH CF₃ C≡C-3-Pyridyl 2263 N CCl CH CH CF₃ C≡C-4-Pyridyl 2264 N CCl CH CH CF₃ C≡C-2-furanyl 2265 N CCl CH CH CF₃ C≡C-3-furanyl 2266 N CCl CH CH CF₃ C≡C-2-thienyl 2267 N CCl CH CH CF₃ C≡C-3-thienyl 2268 N CCl CH CH CF₃ CH═CH-cycPr 2269 N CCl CH CH CF₃ CH═CH-iPr 2270 N CCl CH CH CF₃ CH═CH-nPr 2271 N CCl CH CH CF₃ CH═CH-Bu 2272 N CCl CH CH CF₃ CH═CH-iBu 2273 N CCl CH CH CF₃ CH═CH-tBu 2274 N CCl CH CH CF₃ CH═CH-Et 2275 N CCl CH CH CF₃ CH═CH-Me 2276 N CCl CH CH CF₃ CH═CH-Ph 2277 N CCl CH CH CF₃ CH═CH-2-Pyridyl 2278 N CCl CH CH CF₃ CH═CH-3-Pyridyl 2279 N CCl CH CH CF₃ CH═CH-4-Pyridyl 2280 N CCl CH CH CF₃ CH═CH-2-furanyl 2281 N CCl CH CH CF₃ CH═CH-3-furanyl 2282 N CCl CH CH CF₃ CH═CH-2-thienyl 2283 N CCl CH CH CF₃ CH═CH-3-thienyl 2284 N CCl CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2285 N CCl CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2286 N CCl CH CH CF₃ CH₂CH₂CH₂CH₃ 2287 N CCl CH CH CF₃ CH₂CH₂CH₃ 2288 N CCl CH CH CF₃ CH₂CH₂-cycPr 2289 N CCl CH CH CF₃ CH₂CH₂-tBu 2290 N CCl CH CH CF₃ CH₂CH₂-Ph 2291 N CCl CH CH CF₃ CH₂CH₂-2-Pyridyl 2292 N CCl CH CH CF₃ CH₂CH₂-3-Pyridyl 2293 N CCl CH CH CF₃ CH₂CH₂-4-Pyridyl 2294 N CCl CH CH CF₃ CH₂CH₂-2-furanyl 2295 N CCl CH CH CF₃ CH₂CH₂-3-furanyl 2296 N CCl CH CH CF₃ CH₂CH₂-2-thienyl 2297 N CCl CH CH CF₃ CH₂CH₂-3-thienyl 2298 N C(OCH₃) CH CH CF₃ C≡C-cycPr 2299 N C(OCH₃) CH CH CF₃ C≡C-iPr 2300 N C(OCH₃) CH CH CF₃ C≡C-nPr 2301 N C(OCH₃) CH CH CF₃ C≡C-Bu 2302 N C(OCH₃) CH CH CF₃ C≡C-iBu 2303 N C(OCH₃) CH CH CF₃ C≡C-tBu 2304 N C(OCH₃) CH CH CF₃ C≡C-Et 2305 N C(OCH₃) CH CH CF₃ C≡C-Me 2306 N C(OCH₃) CH CH CF₃ C≡C-Ph 2307 N C(OCH₃) CH CH CF₃ C≡C-2-Pyridyl 2308 N C(OCH₃) CH CH CF₃ C≡C-3-Pyridyl 2309 N C(OCH₃) CH CH CF₃ C≡C-4-Pyridyl 2310 N C(OCH₃) CH CH CF₃ C≡C-2-furanyl 2311 N C(OCH₃) CH CH CF₃ C≡C-3-furanyl 2312 N C(OCH₃) CH CH CF₃ C≡C-2-thienyl 2313 N C(OCH₃) CH CH CF₃ C≡C-3-thienyl 2314 N C(OCH₃) CH CH CF₃ CH═CH-cycPr 2315 N C(OCH₃) CH CH CF₃ CH═CH-iPr 2316 N C(OCH₃) CH CH CF₃ CH═CH-nPr 2317 N C(OCH₃) CH CH CF₃ CH═CH-Bu 2318 N C(OCH₃) CH CH CF₃ CH═CH-iBu 2319 N C(OCH₃) CH CH CF₃ CH═CH-tBu 2320 N C(OCH₃) CH CH CF₃ CH═CH-Et 2321 N C(OCH₃) CH CH CF₃ CH═CH-Me 2322 N C(OCH₃) CH CH CF₃ CH═CH-Ph 2323 N C(OCH₃) CH CH CF₃ CH═CH-2-Pyridyl 2324 N C(OCH₃) CH CH CF₃ CH═CH-3-Pyridyl 2325 N C(OCH₃) CH CH CF₃ CH═CH-4-Pyridyl 2326 N C(OCH₃) CH CH CF₃ CH═CH-2-furanyl 2327 N C(OCH₃) CH CH CF₃ CH═CH-3-furanyl 2328 N C(OCH₃) CH CH CF₃ CH═CH-2-thienyl 2329 N C(OCH₃) CH CH CF₃ CH═CH-3-thienyl 2330 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₂CH₂CH₃ 2331 N C(OCH₃) CH CH CF₃ CH₂CH₂CH(CH₃)₂ 2332 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₂CH₃ 2333 N C(OCH₃) CH CH CF₃ CH₂CH₂CH₃ 2334 N C(OCH₃) CH CH CF₃ CH₂CH₂-cycPr 2335 N C(OCH₃) CH CH CF₃ CH₂CH₂-tBu 2336 N C(OCH₃) CH CH CF₃ CH₂CH₂-Ph 2337 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-Pyridyl 2338 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-Pyridyl 2339 N C(OCH₃) CH CH CF₃ CH₂CH₂-4-Pyridyl 2340 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-furanyl 2341 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-furanyl 2342 N C(OCH₃) CH CH CF₃ CH₂CH₂-2-thienyl 2343 N C(OCH₃) CH CH CF₃ CH₂CH₂-3-thienyl 2344 N CH CH CH CF₃ C≡C-cycPr 2345 N CH CH CH CF₃ C≡C-iPr 2346 N CH CH CH CF₃ C≡C-nPr 2347 N CH CH CH CF₃ C≡C-Et 2348 N CH CH CH CF₃ C≡C-3-Pyridyl 2349 N CH CH CH CF₃ C≡C-2-furanyl 2350 N CH CH CH CF₃ C≡C-3-furanyl 2351 N CH CH CH CF₃ C≡C-2-thienyl 2352 N CH CH CH CF₃ C≡C-3-thienyl *Unless otherwise noted, stereochemistry is (+/−) and in R², all double bonds are trans.

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and in vitro RNA Transcripts

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at −70° C. The concentration of RNA was determined from the A₂₆₀.

Probes

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5′ terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin-CCCTATCATTTTTGGTTTCCAT 3′) was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5′ CTGTCTTACTTTGATAAAACCTC 3′) was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5′ CCCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Streptavidin Coated Plates

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Ma.).

Cells and Virus Stocks

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at −70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA Assay

Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microplate Based Compound Evaluation in HIV-1 Infected MT-2 Cells

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of PDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20 μM.

For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2×concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1 RT Assay Materials and Methods

This assay measures HIV-1 RT RNA dependent DNA polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Reagents

The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/mL and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozen at −20 C.

The 3H dTTP (2.5 mCi/mL in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at −20 C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgCl2, 1 mM DTT, 50 μM EGTA, 5 mg/mL BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) was diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl). All aliquots were frozen at −70 C.

The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 pm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl /well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.

HIV-1 RT Assay

The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/mL BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/mL respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at −20 C. after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 μM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 aM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/mL of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/mL and 5 μM respectively.

Using the Beckman Instruments Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl ). The reactions were incubated at 37 C. and terminated after 45 minutes.

For method 1, 200 μl of an ice-cold solution of 13% trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 mL/wash) with 1 N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 mL of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

For method 2, the assay was terminated with the addition of 175 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

The IC₅₀ values are calculated with the equation:

IC ₅₀ =[Inh]/(1/fractional activity−1)

where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC₅₀ values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC₅₀ values in this range (generally 2 values) were averaged. A compound was considered active if its IC₅₀ was found to be less than 12 μM.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC₉₀. The fold increase in apparent IC₉₀ for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/mL HSA, 1 mg/mL AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC₉₀. It is desirable to have a compound which has high activity against a variety of mutants.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can-be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of Components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the revserse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and eight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound of formula (I):

 or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is O or S; W is N or CR³; X is N or CR⁴; Y is N or CR⁵; Z is N or CR⁶; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R^(a) is selected from H, CF₃CF₂H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰; R^(b) is selected from H, CF₃, CF₂H, C₁₋₄ alkyl, C₃₋₅ cycloalky, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰; alternatively, R^(a) and R^(b) together form —(CH₂)_(n)—; R¹ is selected from CF₃, CF₂H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from —C≡C—R⁸, —CH═CR⁷R⁸, —(CH₂)_(p)CHR⁷R⁸, —CHR⁷C≡C—R⁸, —CHR⁷CH═CHR⁸, and CH═CHCHR⁷R⁸; provided that when either of R^(a) or R^(b) is phenyl, then R¹ is other than C₁₋₄ alkyl and C₃₋₅ cycloalkyl and R² is other than —(CH₂)_(p)CHR⁷R⁸; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7b), C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰; alternatively, R³ and R⁴ together form —OCH₂O—; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form a —OCH₂O— or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, —CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂; R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl; R^(7a), at each occurrence, is selected from H and C₁₋₃ alkyl; R^(7b), at each occurrence, is C₁₋₃ alkyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰; R⁹, at each occurrence, is selected from D (²H), OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰, at each occurrence, is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; R¹¹, and each occurrence, is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷R^(7a), CHO, C(O)CH₃, C(O)NH₂; n, at each occurrence, is selected from 1, 2, 3, 4, and 5; and, p, at each occurrence, is selected from 0, 1, and 2; and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
 2. A method according to claim 1, wherein, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.
 3. A method according to claim 1, wherein, the reverse transcriptase inhibitor is selected from AZT (azidothymidine), 3TC (β-L-3′-thia-2′,3′-dideoxycytidine), efavirenz, rescriptor, ddI (dideoxyinosine), ddC (dideoxycytidine), and d4T (2′,3,′-didehydro-3′-deoxythimidine), and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478 (amprenavir, 4-amino-N-[2(R)-hydroxy-4-phenyl-3(S)-[tetrahydrofuran-3(S)-yloxycarbonylamino]butyl]-N-isobutylbenzenesulfonamide), nelfinavir, KNI-272 (3-(2-Hydroxy-3-{2-[2-(isoquinolin-5-yloxy)-acetylamino]3-methylsulfanyl-propionylamino}-4-phenyl-butyryl)-thiazolidine--4-carboxylic acid tert-butylamide), CGP-61755 (lasinavir), and U-103017 (4-cyano-N-[3-[cyclopropyl (5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]pyran-3-yl)methyl]phenyl]-benzenesulfonamide).
 4. A method according to claim 3, wherein the reverse transcriptase inhibitor is selected from AZT (azidothymidine), efavirenz; rescriptor, and 3TC (β-L-3′-thia-2′,3′dideoxycytidine) and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.
 5. A method according to claim 4, wherein, the reverse transcriptase inhibitor is AZT (azidothymidine).
 6. A method according to claim 4, wherein, the protease inhibitor is indinavir.
 7. The method of claim 1, wherein R^(a) is H; R^(b) is selected from H, CF₃, CF₂H, cyclopropyl, CH═CH₂, and C₁₋₄ alkyl; R¹ is selected from CF₃, CF₂H, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R ¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 8. The method of claim 7, wherein A is O; R¹ is selected from CF₃, CF₂H, C₂H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), NR⁷C(O)OR^(7b); C(O)OR⁷, S(O)_(p)R⁷, SO₂NHR⁷, NR⁷SO₂R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containg from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form —OCH₂O—; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, —CN, F, CF₃, CH₃, and C(O)NH₂; R⁷ is selected from H and CH₃; R^(7a) is selected from H and CH₃; R^(7b) is CH₃; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(—OCH₂CH₂O—), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰; R⁹ is selected from D, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷R^(7a), and C(O)CH₃; and, p is selected from 1and
 2. 9. The method of claim 8, wherein R^(b) is selected from H, CF₃, CF₂H, cyclopropyl, CH═CH₂, CH₃, and CH₂CH₃; R¹ is selected from CF₃, CF₂H, and cyclopropyl; R² is selected from —C≡C—R⁸ and trans-CH═CR⁷R⁸; R³ is selected from H, F, Cl, Br, and I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C≡CH, OCH₃, OCF₃, —CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷R^(7a), C(O)OR⁷, NR⁷SO₂R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³and R⁴ together form —OCH₂O—; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷R^(7a), C(O)CH₃, and C(O)NH₂.
 10. The method of claim 9, wherein the compound of Formula (I) is selected from 5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 5-Isopropylethynyl-5-trifluoromethyl-6,7-difluoro-1,5-dihydro-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifloromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(triflucromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2 (3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoroinethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methy-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cycloprcpylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cycloprcpylethynyl)-1,5-dihydro-3-ethyl-5-(trifluaromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; and, rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; or a pharmaceutically acceptable salt form thereof.
 11. The method of claim 1, wherein the compound is of formula II:

or a stereoisomer or pharmaceutically acceptable salt form thereof.
 12. The method of claim 1, wherein the compound is of formula IIa:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R¹ is CF₃.
 13. A method according to claim 9, wherein, the reverse transcriptase inhibitor is a nucleoside reerse transcriptase inhibitor.
 14. A method according to claim 9, wherein, the reverse transcriptase inhibitor is selected from AZT (azidothymidine), 3TC (β-L-3′-thia-2′,3′-dideoxycytidine), efavirenz, rescriptor, ddI (dideoxyinosine), ddC (dideoxycytidine), and d4T (2′,3′-didehydro-3′-deoxythimidine), and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478 (amprenavir, 4-amino-N-[2(R)-hydroxy-4-phenyl-3(S)-[tetrahydrofuran-3(S)-yloxycarbonylamino]butyl]-N-isobutylbenzenesulfonamide), nelfinavir, KNI-272 (3-(2-Hydroxy-3-{2-[2-(isoquinolin-5-yloxy)-acetylamino]-3-methylsulfanyl-propionylamino}-4-phenyl-butyryl)-thiazolidine-4-carboxylic acid tert-butylamide), CGP-61755 (lasinavir), and U-103017 (4-cyano-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]pyran-3-yl)methyl]phenyl]-benzenesulfonamide).
 15. A method according to claim 14, wherein, the reverse transcriptase inhibitor is selected from AZT (azidothymidine), efavirenz, rescriptor, and 3TC (β-L-3′-thia-2′,3′-dideoxycytidine) and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.
 16. A method according to claim 15, wherein, the reverse transcriptase inhibitor is AZT (azidothymidine).
 17. A method according to claim 15, wherein, the protease inhibitor is indinavir. 